From c6b17f382dc7f16f23f3874f05eacbc93a8e8de8 Mon Sep 17 00:00:00 2001 From: Manuel Holtgrewe Date: Fri, 2 Feb 2024 08:03:13 +0100 Subject: [PATCH] fix: make PDF documentation build and remove some WIP docs (#368) (#423) --- .readthedocs.yaml | 1 + docs/acmg_cnvs_criteria.rst | 9 - docs/acmg_cnvs_details.rst | 356 --------- docs/acmg_seqvars_criteria.rst | 1122 ---------------------------- docs/acmg_seqvars_details.rst | 616 --------------- docs/conf.py | 6 + docs/doc_manual.rst | 2 + docs/img/Tayoun-2018-Figure-1.png | Bin 1590847 -> 0 bytes docs/img/Walker-2023-Figure-4.png | Bin 140421 -> 0 bytes docs/img/Walker-2023-Figure-5.png | Bin 321906 -> 0 bytes docs/img/Walker-2023-Table-2.png | Bin 156630 -> 0 bytes docs/img/Walker-2023-Table-3-1.png | Bin 269381 -> 0 bytes docs/img/Walker-2023-Table-3-2.png | Bin 94297 -> 0 bytes docs/index.rst | 10 - 14 files changed, 9 insertions(+), 2113 deletions(-) delete mode 100644 docs/acmg_cnvs_criteria.rst delete mode 100644 docs/acmg_cnvs_details.rst delete mode 100644 docs/acmg_seqvars_criteria.rst delete mode 100644 docs/acmg_seqvars_details.rst delete mode 100644 docs/img/Tayoun-2018-Figure-1.png delete mode 100644 docs/img/Walker-2023-Figure-4.png delete mode 100644 docs/img/Walker-2023-Figure-5.png delete mode 100644 docs/img/Walker-2023-Table-2.png delete mode 100644 docs/img/Walker-2023-Table-3-1.png delete mode 100644 docs/img/Walker-2023-Table-3-2.png diff --git a/.readthedocs.yaml b/.readthedocs.yaml index 301a9a93..18fe5491 100644 --- a/.readthedocs.yaml +++ b/.readthedocs.yaml @@ -10,6 +10,7 @@ sphinx: configuration: docs/conf.py formats: + - pdf - epub python: diff --git a/docs/acmg_cnvs_criteria.rst b/docs/acmg_cnvs_criteria.rst deleted file mode 100644 index 1cb55a99..00000000 --- a/docs/acmg_cnvs_criteria.rst +++ /dev/null @@ -1,9 +0,0 @@ -.. _acmg_cnvs_criteria: - -================= -AMCG CNV Criteria -================= - -See :ref:`acmg_cnvs_details` for full information on the criteria. - -We implement the ACGM criteria for CNVs from Riggs et al. (2020) using the data listed in :ref:`acmg_cnvs_details`. diff --git a/docs/acmg_cnvs_details.rst b/docs/acmg_cnvs_details.rst deleted file mode 100644 index 543e22a7..00000000 --- a/docs/acmg_cnvs_details.rst +++ /dev/null @@ -1,356 +0,0 @@ -.. _acmg_cnvs_details: - -================ -AMCG CNV Details -================ - -This section contains detailed information about the ACMG assessment criteria for CNVs. - -.. _acmg_cnvs_details-data: - ----- -Data ----- - -The following data is used for the classification: - -.. list-table:: Tools and datasources used - - * - Data - - Datasource - * - Gene Transcripts - - RefSeq / ENSEMBL - * - Pathogenic / Benign Regions - - ClinVar SVs - * - Population Variants - - gnomAD SVs, dbVar - * - Disease Gene Annotation - - NCBI MedGen mim2gene - * - HI/TS Regions - - ClinGen Curation - -.. _acmg_cnvs_details-references: - ----------- -References ----------- - -Literature with direct ACMG / ACGS / ClinGen relationship - -- Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, Raca G, Ritter DI, South ST, Thorland EC, Pineda-Alvarez D, Aradhya S, Martin CL. - *Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).* - Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6. Erratum in: Genet Med. 2021 Nov;23(11):2230. PMID: 31690835; PMCID: PMC7313390. - -Further Supporting Literature - -- Gurbich TA, Ilinsky VV. - *ClassifyCNV: a tool for clinical annotation of copy-number variants.* - Sci Rep. 2020 Nov 23;10(1):20375. doi: 10.1038/s41598-020-76425-3. PMID: 33230148; PMCID: PMC7683568. -- Fan C, Wang Z, Sun Y, Sun J, Liu X, Kang L, Xu Y, Yang M, Dai W, Song L, Wei X, Xiang J, Huang H, Zhou M, Zeng F, Huang L, Xu Z, Peng Z. - AutoCNV: a semiautomatic CNV interpretation system based on the 2019 ACMG/ClinGen Technical Standards for CNVs. - BMC Genomics. 2021 Oct 6;22(1):721. doi: 10.1186/s12864-021-08011-4. PMID: 34615484; PMCID: PMC8496072. -- Danis D, Jacobsen JOB, Balachandran P, Zhu Q, Yilmaz F, Reese J, Haimel M, Lyon GJ, Helbig I, Mungall CJ, Beck CR, Lee C, Smedley D, Robinson PN. - *SvAnna: efficient and accurate pathogenicity prediction of coding and regulatory structural variants in long-read genome sequencing.* - Genome Med. 2022 Apr 28;14(1):44. doi: 10.1186/s13073-022-01046-6. PMID: 35484572; PMCID: PMC9047340. - ----------------- -Score Evaluation ----------------- - -.. list-table:: - - * - Level - - Range - * - Pathogenic - - >=0.99 - * - Likely Pathogenic - - >=0.90, <0.99 - * - Variant of Uncertain Significance - - >=-0.89, <0.89 - * - Likely Benign - - >=-0.99, <-0.89 - * - Benign - - <= -1.00 - -.. _acmg_cnvs_details-loss: - ----------------- -Copy Number Loss ----------------- - -.. _acmg_cnvs_details-loss-1: - -Section 1: Genomic Content -========================== - -.. _acmg_cnvs_details-loss-2: - -- Evidence type: Copy number loss content - -Subsections - -- 1A. Contains protein-coding or other known functionally important elements -- 1B. Does NOT contain protein-coding or any known functionally important elements - -Section 2: Overlapping Genes or Regions -======================================= - -(Skip to Section 3 if your copy number loss DOES NOT overlap these types of genes/regions) - -- 2A-E: Overlap with ESTABLISHED HI genes or genomic regions and consideration of reason for referral - - - 2A. Complete overlap of an established HI gene/genomic region - - 2B. Partial overlap of an established HI genomic region - - - The observed CNV does NOT contain the known causative gene or critical region for this established HI genomic region OR - - Unclear if known causative gene or critical region is affected OR - - No specific causative gene or critical region has been established for this HI genomic region - - - 2C. Partial overlap with the 5' end of an established HI gene (3' end of the gene not involved)… - - - 2C-1. …and coding sequence is involved - - 2C-2. …and only the 5' UTR is involved - - - 2D. Partial overlap with the 3' end of an established HI gene (5' end of the gene not involved) … - - - 2D-1 …and only the 3' untranslated region is involved. - - 2D-2. …and only the last exon is involved. - Other established pathogenic variants have been reported in this exon. - - 2D-3. …and only the last exon is involved. - No other established pathogenic variants have been reported in this exon. - - 2D-4. …and it includes other exons in addition to the last exon. - Nonsense-mediated decay is expected to occur. - - - 2E. Both breakpoints are within the same gene (intragenic CNV; gene-level sequence variant) - -- 2F-G: Overlap with ESTABLISHED benign genes or genomic regions - - - 2F. Completely contained within an established benign CNV region - - 2G. Overlaps an established benign CNV, but includes additional genomic material - -- 2H: Haploinsufficiency Predictors - - - 2H. Two or more HI predictors suggest that AT LEAST ONE gene in the interval is haploinsufficient (HI) - -.. _acmg_cnvs_details-loss-3: - -Section 3: Evaluation of Gene Number -==================================== - -- Evidence type: Number of protein-coding RefSeq genes wholly or partially included in the copy number loss - -Subsections: - -- 3A. 0-24 genes -- 3B. 25-34 genes -- 3C. 35+ genes - -.. _acmg_cnvs_details-loss-4: - -Section 4: Evaluation of Case Data -================================== - -- 4A-C: Individual case evidence - de novo occurrences. - - Reported proband (from literature, public databases, or internal lab data) has either: - - - A complete deletion of or a LOF variant within gene encompassed by the observed copy number loss OR - - an overlapping copy number loss similar in genomic content to the observed copy number loss AND… - - Subsections: - - - 4A. …the reported phenotype is highly specific and relatively unique to the gene or genomic region - - 4B. …the reported phenotype is consistent with the gene/genomic region, is highly specific, but not necessarily unique to the gene/genomic region - - 4C. …the reported phenotype is consistent with the gene/genomic region, but not highly specific and/or with high genetic heterogeneity - -- 4D: Individual case evidence - inconsistent phenotype - - - 4D.…the reported phenotype is NOT consistent with what is expected for the gene/genomic region or not consistent in general - -- 4E: Individual case evidence - unknown inheritance - - - 4E. Reported proband has a highly specific phenotype consistent with the gene/genomic region, but the inheritance of the variant is unknown. - -- 4F-H: Individual case evidence - segregation among similarly affected family members - - - 4F. 3-4 observed segregations - - 4G. 5-6 observed segregations - - 4H. 7 or more observed segregations - -- 4I-K: Individual case evidence - Non-Segregations - - - 4I. Variant is NOT found in another individual in the proband's family AFFECTED with a consistent, specific, well-defined phenotype (no known phenocopies) - - 4J. Variant IS found in another individual in the proband's family UNAFFECTED with the specific, well-defined phenotype observed in the proband - - 4K. Variant IS found in another individual in the proband's family UNAFFECTED with the non-specific phenotype observed in the proband - -- 4L-O: Case-control and population evidence - - - 4L. Statistically significant increase amongst observations in cases (with a consistent, specific, well-defined phenotype) compared to controls - - 4M. Statistically significant increase amongst observations in cases (without a consistent, non-specific phenotype OR unknown phenotype) compared to controls - - 4N. No statistically significant difference between observations in cases and controls - - 4O. Overlap with common population variation - -.. _acmg_cnvs_details-loss-5: - -Section 5: Inheritance / Family History -======================================= - -- 5A: Observed copy number loss is DE NOVO - - - 5A. Use appropriate category from de novo scoring section in Section 4. - -- 5D: Observed copy number loss is INHERITED - - - 5B. Patient with specific, well-defined phenotype and no family history. - CNV is inherited from an apparently unaffected parent. - - 5C. Patient with non-specific phenotype and no family history. - CNV is inherited from an apparently unaffected parent. - - 5D. CNV segregates with a consistent phenotype observed in the patient's family. - -- 5E: Observed copy number loss - NON-SEGREGATIONS - - - 5E. Use appropriate category from non-segregation section in Section 4. - -- 5F-H: Other - - - 5F. Inheritance information is unavailable or uninformative. - - 5G. Inheritance information is unavailable or uninformative. - The patient phenotype is non-specific, but is consistent with what has been described in similar cases. - - 5H. Inheritance information is unavailable or uninformative. - The patient phenotype is highly specific and consistent with what has been described in similar cases. - -.. _acmg_cnvs_details-gain: - ----------------- -Copy Number Gain ----------------- - -.. _acmg_cnvs_details-gain-1: - -Section 1: Genomic Content -========================== - -- Evidence type: Copy Number Gain Content - -Subsections: - -- 1A: Contains protein-coding or other known functionally important elements -- 2B: Does NOT contain protein-coding or any known functionally important elements - -.. _acmg_cnvs_details-gain-2: - -Section 2: Overlapping Genes or Regions -======================================= - -- 2A-B: Overlap with ESTABLISHED TS genes or genomic regions - - - 2A: Complete overlap; the TS gene or minimal critical region is fully contained within the observed copy number gain - - 2B: artial overlap of an established TS region - - - The observed CNV does NOT contain the known causative gene or critical region for this established TS genomic region OR - - Unclear if the known causative gene or critical region is affected OR - - No specific causative gene or critical region has been established for this TS genomic region - -- 2C-G: Overlap with ESTABLISHED benign copy number gain genes or genomic regions - -- 2C: Identical in gene content to the established benign copy number gain - - - 2D: Smaller than established benign copy number gain, breakpoint(s) does not interrupt protein-coding genes - - 2E: Smaller than established benign copy number gain, breakpoint(s) potentially interrupts protein-coding gene - - 2F: Larger than known benign copy number gain, does not include additional protein-coding genes - - 2G: Overlaps a benign copy number gain but includes additional genomic material - -- 2H: Overlap with ESTABLISHED HI gene(s) - - - 2H: HI gene fully contained within observed copy number gain - -- 2I-K: Breakpoint(s) within ESTABLISHED HI genes - - - 2I: Both breakpoints are within the same gene (gene-level sequence variant, possibly resulting in loss of function (LOF)) - - 2J: One breakpoint is within an established HI gene, patient's phenotype is either inconsistent with what is expected for LOF of that gene OR unknown - - 2K: One breakpoint is within an established HI gene, patient's phenotype is highly specific and consistent with what is expected for LOF of that gene - -- 2L: Breakpoints within other gene(s) - - 2L: One or both breakpoints are within gene(s) of no established clinical significance - -(Skip to Section 3 if your copy number loss DOES NOT overlap these types of genes/regions) - -.. _acmg_cnvs_details-gain-3: - -Section 3: Evaluation of Gene Number -==================================== - -- Evidence type: Number of protein-coding RefSeq genes wholly or partially included in the copy number gain - -Subsections: - -- 3A: 0-34 genes -- 3B: 35-49 genes -- 3C: 50 or more genes - -.. _acmg_cnvs_details-gain-4: - -Section 4: Evaluation of Case Data -================================== - -- 4A-C: Individual case evidence - de novo occurrences - - - 4A. …the reported phenotype is highly specific and relatively unique to the gene or genomic region. - - 4B. …the reported phenotype is consistent with the gene/genomic region, is highly specific, but is not necessarily unique to the gene/genomic region - - 4C. …the reported phenotype is consistent with the gene/genomic region, but not highly specific and/or with high genetic heterogeneity - -- 4D: Individual case evidence - inconsistent phenotype - - - 4D. …the reported phenotype is NOT consistent with the gene/genomic region or not consistent in general - -- 4E: Individual case evidence - unknown inheritance - - - 4E. Reported proband has a highly specific phenotype consistent with the gene/genomic region, but the inheritance of the variant is unknown - -- 4F-H: Individual case evidence - segregation among similarly affected family members - - - 4F. 3-4 observed segregations - - 4G. 5-6 observed segregations - - 4H. 7 or more observed segregations - -- 4I-K: Individual case evidence - Non-Segregations - - - 4I. Variant is NOT found in another individual in the proband's family AFFECTED with a consistent, specific, well-defined phenotype (no known phenocopies) - - 4J. Variant IS found in another individual in the proband's family UNAFFECTED with the specific, well-defined phenotype observed in the proband - - 4K. Variant IS found in another individual in the proband's family UNAFFECTED with the non-specific phenotype observed in the proband - -- 4L-O: Case-Control and Population Evidence - - - 4L. Statistically significant increase amongst observations in cases (with a consistent, specific, well-defined phenotype) compared to controls - - 4M. Statistically significant increase amongst observations in cases (with a consistent, non-specific phenotype or unknown phenotype) compared to controls - - 4N. No statistically significant difference between observations in cases and controls - - 4O. Overlap with common population variation - -.. _acmg_cnvs_details-gain-5: - -Section 5: Inheritance / Family History -======================================= - -- 5A: Observed copy number gain is DE NOVO - - - 5A. Use appropriate category from de novo scoring section in Section 4. - -- 5B-D: Observed copy number gain is INHERITED - - - 5B. Patient with a specific, well-defined phenotype and no family history. - Copy number gain is inherited from an apparently unaffected parent. - - 5C. Patient with non-specific phenotype and no family history. - Copy number gain is inherited from an apparently unaffected parent. - - 5D. CNV segregates with consistent phenotype observed in the patient's family. - -- 5E: Observed copy number gain - Non-SEGREGATIONS - - - 5E. Use appropriate category from non-segregation section in Section 4. - -- 5F-H: Other: - - - 5F. Inheritance information is unavailable or uninformative - - 5G. Inheritance information is unavailable or uninformative. - The patient phenotype is non-specific, but is consistent with what has been described in similar cases. - - 5H. Inheritance information is unavailable or uninformative. - The patient phenotype is highly specific and consistent with what has been described in similar cases. diff --git a/docs/acmg_seqvars_criteria.rst b/docs/acmg_seqvars_criteria.rst deleted file mode 100644 index 7e9a4a56..00000000 --- a/docs/acmg_seqvars_criteria.rst +++ /dev/null @@ -1,1122 +0,0 @@ -.. _acmg_seqvars_criteria: - -============================== -ACMG Sequence Variant Criteria -============================== - -This section describes the criteria as implemented for the automated classification of ACMG sequence variants. - -A large focus is given towards the transparency to the user. -The user is always given a report of the evidence for and against a given criterion. -Even if not further described, the reason for skipping a criterion is always reported (e.g., BA1 disables all other benign criteria, or if a criterion is only valid for missense variants). - -.. _acmg_seqvars_criteria-inheritance: - -------------------- -Mode of Inheritance -------------------- - -The mode of inheritance for a is derived from the following list of sources. -The sources are iterated in the order given below and the first one with a match is used for deriving mode of inheritance. - -1. **NHGRI CGD** - The `National Human Genome Research Institute Clinical Genomic Database `__ -2. **ClinGen Disease Validity** `Website `__ -3. **EBI gene2phenotype** `Website `__ -4. **ClinGen GenCC** `Website `__ -5. **Genomics England PanelApp** `Web-App `__ -6. **Domino** is a machine learning method for prediction of mode of inheritance and described in `PMID:28985496 `__. - We use the thresholds from `PMID:30376034 `__. - - - dominant: if score >= 0.5934 - - recessive: if score <= 0.3422 - - dominant/recessive: if score is between 0.3422 and 0.5934 - -.. _acmg_seqvars_criteria-inheritance-literature: - -Literature -========== - - -.. _acmg_seqvars_criteria-frequency: - ----------------- -Allele Frequency ----------------- - -The databases gnomAD exomes and genomes will be used to derived allele frequencies. -We trust the gnomAD quality control pipeline and filter solely above the gnomAD variant annotation. -Frequencies are considered valid if: - -- allele number is >=2000 -- gnomAD quality filter is PASS - -The criteria BA1 and BS1 will ignore the following "bottlenecked" populations: -Amish (ami), Ashkenazi Jewish (asj), European Finnish (fin), Middle Eastern (mid), and "Remaining Individuals (rmi) groups". - -.. _acmg_seqvars_criteria-calibration: - ------------ -Calibration ------------ - -We currently do not have our own calibration yet. -This is a big TODO once we have all the data. - --------------------- -Transcript Selection --------------------- - -We use the MANE Plus Clinical set of transcripts for the genes that have such information. -Otherwise, we use the longest transcript as the MANE transcript and consider all alternate RefSeq transcripts. - -MANE annotation is not available for GRCh37 and will not be provided by ENSEMBL/NCBI. -We thus map the MANE (and MANE Plus Clinical) transcripts from GRCh38 by using the latest version of the transcript with the same identifier. -If mapping either MANE or any of the MANE Plus Clinical transcripts fails then we fall back to the longest transcript rule. - -.. _acmg_seqvars_criteria-patho-predictions: - -------------------------- -Pathogenicity Predictions -------------------------- - -We currently use the thresholds from :footcite:t:`pejaver:2022` only. - -Once we have our own calibration, we can extend our predictions to novel tools such as AlphaMissense. - -.. _acmg_seqvars_mods: - ------------------------------- -Code Modification Nomenclature ------------------------------- - -In accordance with ClinGen Sequence Variant Interpretation Work Group (2017), modification codes are used. -That is, for a criterion ``${CRIT}``, the modification codes ``${CRIT}_Supporting``, ``${CRIT}_Moderate``, ``${CRIT}_Strong``, ``${CRIT}_VeryStrong``. - -.. _acmg_seqvars_criteria-rules: - --------------------- -Rules / Point System --------------------- - -We consider three rule systems: - -- The original ACMG 2015 rules -- The ACGS 2020 rules -- The 2020 Point system described by Tavtigian et al. (2020) - -ACMG 2015 Rules -=============== - -The following rules have been defined in Richards et al. (2015). - -Pathogenic ----------- - -If one of the following criteria 1-3 are fulfilled. - -1. 1 very strong (PVS1) AND one of the following - a. >=1 strong (PS1-PS4) - b. >=2 moderate (PM1-PM6) - c. >=1 moderate (PM1-PM6) AND >=1 supporting (PP1-PP5) - d. >=2 supporting (PP1-PP5) -2. >=2 strong (PS1-PS4) -3. 1 strong (PS1-PS4) AND - a. >=3 moderate (PM1-PM6) - b. 2 moderate (PM1-PM6) AND >=2 supporting (PP1-PP5) - c. 1 moderate (PM1-PM6) AND >=4 supporting (PP1-PP5) - -Likely Pathogenic ------------------ - -If one of the following criteria 1-7 are fulfilled. - -1. 1 very strong (PVS1) AND 1 moderate (PM1-PM6) -2. 1 strong (Ps1-PS4) AND 1-2 moderate (PM1-PM6) -3. 1 strong (PS1-PS4) AND >=2 supporting (PP1-PP5) -4. >=3 moderate (PM1-PM6) -5. 2 moderate (PM1-PM6) AND >=2 supporting (PP1-PP5) -6. 1 moderate (PM1-PM6) AND >=4 supporting (PP1-PP5) - -Benign ------- - -If one of the following criteria 1-2 are fulfilled. - -1. 1 standalone (BA1) -2. >=2 strong (BS1-BS4) - -Likely Benign -------------- - -If one of the following criteria 1-2 are fulfilled. - -1. 1 strong (BS1-BS4) AND 1 supporting (BP1-BP7) -2. >=2 supporting (BP1-BP7) - -Uncertain Significance ----------------------- - -If if one of the following criteria 1-2 are fulfilled. - -1. Other criteria shown above are not met -2. the criteria for benign and pathogenic are contradictory - -ACGS 2020 Rules -=============== - -The following is a refinement of the rules above set by the Ellard et al. (2020). - -Pathogenic ----------- - -1. 1 very strong (PVS) AND one of the following - a. >=1 strong - b. >=1 moderate - c. >=2 supporting -2. >=3 strong -3. 2 strong AND one of the following - a. >=1 moderate - b. >=2 supporting -4. 1 strong AND one of the following - a. >=3 moderate - b. >=2 moderate AND >=2 supporting - c. >=1 moderate AND >=4 supporting - -Likely Pathogenic ------------------ - - -1. >=2 strong -2. 1 strong AND one of teh following - a. 1-2 moderate OR - b. >=2 supporting -3. >=3 moderate OR - a. 2 moderate AND >=2 supporting - b. 1 modereate AND >=4 supporting - -Tavtigian et al. (2020) Rules -============================= - -Alternatively, Tavtigian et al. (2020) formulated the rules as an integer point system. - -Table 2 from this manuscript gives point values: - -.. list-table:: Points per proband - - * - evidence strength - - points pathogenic - - points benign - * - indeterminate - - 0 - - 0 - * - supporting - - 1 - - -1 - * - moderate - - 2 - - -2 - * - strong - - 4 - - -4 - * - very strong - - 8 - - -8 - -The point-based variant classification categories are then given in their Table 3: - -.. list-table:: Categories and point ranges - - * - category - - point ranges - * - pathogenic - - >= 10 - * - likely pathogenic - - 6 to 9 - * - uncertain significance - - 0 to 5 - * - likely benign - - -1 to -6 - * - benign - - <= -7 - --------- -Criteria --------- - -.. _acmg_seqvars_criteria-pvs1: - -PVS1 (null variant) -=================== - -Original Definition -------------------- - - Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. - - Caveats: - - - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) - - Use caution interpreting LOF variants at the extreme 3' end of a gene - - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact - - Use caution in the presence of multiple transcripts - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- Criterion establishes whether LoF is a known mechanism of disease: - - If at least 2 LoF variants are reported in ClinVar with two or more stars then this criterion is triggered. - - If the gnomAD LOF Observed/Expected is less than 0.7555 then this criterion is triggered. -- Criterion establishes whether a stop_gain variant introduced nonsense mediated decay (NMD) consistent with Abou Youn et al. (2018) and the VEP NMD plugin. - - If the variant is on chrMT then it cannot be NMD. - - If the variant is not_stop gain then then it cannot be NMD, else: - - If the variant is in the last exon of the transcript then it is predicted to escape NMD. - - If the variant falls 50bp upstream of the penuultimate (second to the last) exon then it is predicted to escape NMD. - - If the variant falls int the first 100 coding bases in teh transcript then it is predicted to escape NMD. - - If the variant is in an intronless transcript, meaning only one exon exists in the transcript, then it is predicted to escape NMD. - - Else, the variant is predicted to be NMD. -- The MANE Plus Clinical transcripts are used for "biologically relevant transcripts" in this criterion. - -Implemented Criterion ---------------------- - -While the original description is somewhat vague, the specification in Abou Tayoun et al. (2018) is more precise but complex to implement. -We plan to implement it as closely as possible. - -TODO: full specification - -Literature ----------- - -- Richards et al. (2015) describes the original criterion. -- Abou Tayoun et al. (2018) describe refined criteria for PVS1. -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. -- The following are from the VEP NMD plugin: - - Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles (Coban-Akdemir, 2018) - - The criteria and impact of nonsense-mediated mRNA decay in human cancers (Lindeboom, 2016) - -User Report ------------ - -The following information is reported to the user: - -- The evidence for / against LoF as disease mechanism. -- Whether NMD and NMD escape is predicted for this variant and the reason. -- The use of MANE Plus Clinical or alternate transcripts for locating alternate start codons. -- Further information of interest from the Abou Tayoun et al. (2018) decision tree. - -Caveats -------- - -- We use the thresholds from `PMID:30376034 `__ but should reconsider, e.g., switching to LOEUF here with our own thresholds. -- This is currently not implementing the full criteria set from Abou Tayoun et al. (2018). - -Notes ------ - -- If this criterion is triggered then PP3 and PM4 will be disabled. - -.. _acmg_seqvars_criteria-ps1: - -PS1 (same amino acid) -===================== - -Original Definition -------------------- - - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. - - Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the variant is not a missense variant then this criterion is skipped. - -Implemented Criterion ---------------------- - -- Consider all equivalent missense variants in ClinVar. -- If at least one of the variant then this criterion is triggered. - - If the variant has zero stars in ClinVar then we report PS1_Supporting only - - If the variant has only one star in ClinVar then we report PS1_Moderate only - - If the variant has two stars in ClinVar then we report PS1 - - If the variant has three stars or above in ClinVar then we report PS1_VeryStrong - -User Report ------------ - -- The selected variant in ClinVar and with assessment its star status with accession. -- All alternate variants in Clinvar with assessments and star status with accessions. - -Literature ----------- - -N/A - -Caveats -------- - -- The wording of "established pathogenic" variant is not clear so we use the steps from above. -- Note that this also depends on disease match which the user must confirm manually. - -.. _acmg_seqvars_criteria-ps2: - -PS2 (confirmed *de novo*) -========================= - -No automation has been implemented. - -Original Definition -------------------- - - De novo (both maternity and paternity confirmed) in a patient with the disease and no family history - - Note: Confirmation of paternity only is insufficient. - Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-ps3: - -PS3 (functional studies) -======================== - -No automation has been implemented. - -Original Definition -------------------- - - Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. - - Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-ps4: - -PS4 (prevalence) -================ - -No automation has been implemented. - -Original Definition -------------------- - - The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls - - Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. - - Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-pm1: - -PM1 (hotspot) -============= - -Original Definition -------------------- - - Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the variant is on chrMT then this criterion is skipped according to McCormick et al. (2020). - -Implemented Criterion ---------------------- - -- If the variant is within a hotspot (at least 4 pathogenic missense/in-frame variants within 25bp radius) then this criterion is triggered. -- If the variant is within an annotated UniProt domain and the domain contains at least 2 pathogenic variants then this criterion is triggered. - -User Report ------------ - -- The hotspot region definition and the number of pathogenic variants in the region. - -Literature ----------- - -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -Caveats -------- - -- We currently use the threshold from `PMID:30376034 `__ and are lacking our own calibration. - -.. _acmg_seqvars_criteria-pm3: - -PM3 (recessive in *trans*) -========================== - -No automation has been implemented. - -Original Definition -------------------- - - For recessive disorders, detected in trans with a pathogenic variant. - - Note: This requires testing of parents (or offspring) to determine phase. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-pm4: - -PM4 (protein length) -==================== - -Original Definition -------------------- - - Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If PVS1 was triggered then this criterion is skipped to avoid double counting. -- If the variant is not an in-frame indel and not a stop-loss variant then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the variant is an in-frame indel - - If the variant is inside a repeat masked region then it is skipped - - If the variant is inside a repeat as annotated by UniProt then it is skipped - - Otherwise, this criterion is triggered. -- If the variant is a stop-loss variant then this criterion is triggered. - -User Report ------------ - -- Any reasons for skipping in repeat regions. -- The transcript identifier. - -Literature ----------- - -N/A - -Caveats -------- - -- Richards et al. (2015) state that the size of the indel and amount of change in amino acids should influence the classification. - We currently do not have this implemented. - -.. _acmg_seqvars_criteria-pm5: - -PM5 (overlapping missense) -========================== - -Original Definition -------------------- - - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. - - Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the variant is on a nuclear chromosome - - If it is not a missense variant then this criterion is skipped. -- If the variant is on chrMT and not missense and not on a tRNA gene then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the variant is on a nuclear chromosome: - - If the variant is at the same position as a pathogenic missense variant then this criterion is triggered. -- If the variant is on chrMT: - - If the variant is a missense variant and at the same position as a pathogenic one then the criterion is triggered. - - If the variant is on a tRNA gene and at the same position as a pathogenic one then the criterion is triggered as PM5_Supporting. - -User Report ------------ - -- The overlapping variant used for criterion. -- Any alternative overlapping variants not chosen. - -Literature ----------- - -- Richards et al. (2018) describes the criterion for nuclear chromosomes. -- McCormick et al. (2020) describes the criterion for chrMT. - -Caveats -------- - -N/A - -.. _acmg_seqvars_criteria-pm6: - -PM6 (assumed *de novo*) -======================= - -No automation has been implemented. - -Original Definition -------------------- - - Assumed de novo, but without confirmation of paternity and maternity. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-pm2: - -PM2_Supporting (absent from controls) -===================================== - -Original Definition -------------------- - - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- Determine :ref:`acmg_seqvars_criteria-inheritance` for the gene. -- Determine :ref:`acmg_seqvars_criteria-frequency`. -- If the allele frequency is invalid then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the variant is on a nuclear chromosome: - - If the gene is marked as recessive or X-linked: - - If the variant allele count is <=4 then this criterion is triggered. - - If the gene is marked as dominant: - - If the homozygous allele count is <=1 then this criterion is triggered. - - If the allele frequency is less than 0.0001 then this criterion is triggered. -- If the variant is on chrMT: - If the variant frequency is below 0.00002=0.002%=1/50,000 then this criterion is triggered. - -User Report ------------ - -- The values and thresholds used by the criterion even if failed. - -Literature ----------- - -- Richards et al. (2015) describes the original criterion. -- ClinGen Sequence Variant Interpretation Work Group (2020): SVI Recommendation for Absence/Rarity (PM2) - Version 1.0 describes the downgrade to supporting. -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -Caveats -------- - -- We currently use the threshold from `PMID:30376034 `__ and are lacking our own calibration. -- This criterion has been downgraded by default to supporting from strong in accordance to ClinGen Sequence Variant Interpretation Work Group (2020): *SVI Recommendation for Absence/Rarity (PM2) - Version 1.0* - -.. _acmg_seqvars_criteria-pp1: - -PP1 (cosegregation) -=================== - -No automation has been implemented. - -.. _acmg_seqvars_criteria-pp2: - -PP2 (missense) -============== - -Original Definition -------------------- - - Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the variant is on chrMT then this criterion is skipped according to McCormick et al. (2020). -- If the variant is not a missense variant then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the ratio of pathogenic missense variants over all non-VUS missense variants is greater than 0.808 then this criterion is triggered. - -User Report ------------ - -- Report the ratio of pathogenic missense variants over all non-VUS missense variants. - -Literature ----------- - -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -Caveats -------- - -- We currently use the threshold from `PMID:30376034 `__ and are lacking our own calibration. - -Notes ------ - -- This criterion is similar to :ref:`acmg_seqvars_criteria-bp1` - -.. _acmg_seqvars_criteria-pp3: - -PP3 (*in silico* predictions) -============================= - -Original Definition -------------------- - - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). - - Caveats: - - - As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. - - PP3 can be used only once in any evaluation of a variant. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the criterion PVS1 was triggered then this criterion is skipped. -- If the variant is on chrMT then it is skipped, as we don't have calibration for chrMT yet. -- If the variant is not found in dbNSFP or CADD precomputed scores then it is skipped as we don't have calibration for chrMT yet. - -Implemented Criterion ---------------------- - -An initial prediction is fist done using the general purpose pathogenicity predictors. - -- If we have a score from the following, then the prediction is used (in descending order of priority): - - REVEL, MutPred2, CADD, BayesDel, VEST4, ..., PhyloP - - we will use the modifiers from :footcite:t:`pejaver:2022` -- If predictions are missing then then PhyloP of the position of the variant is used as a fallback. - -Then, for splicing the following is done. - -- If a SpliceAI prediction is performed then it is interpreted according to :footcite:t:`walker:2023`. - -The highest-scoring variant is used for the final prediction. - -User Report ------------ - -- The scores and predictions from the predictors. - -Caveats -------- - -- As described in :ref:`acmg_seqvars_criteria-patho-predictions`, we are currently limited to the precomputed threshold from the literature. - This hinders us in adopting AlphaMissense effectively, for example. -- We need to compute accuracy to rank the implemented methods. -- We need our own calibration for chrMT. - -Notes ------ - -- This criterion is similar to :ref:`acmg_seqvars_criteria-bp4` - -.. _acmg_seqvars_criteria-pp4: - -PP4 (monogenetic) -================= - -No automation has been implemented. - -.. _acmg_seqvars_criteria-ba1: - -BA1 (5% frequency) -================== - -Original Definition -------------------- - - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- The variant is absent from the exception list from Ghosh et al. (2018). - If the variant is present on this list, then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the variant is nuclear (not on chrMT) - - If the allele frequency is above 0.05 in gnomAD global population then this criterion is triggered. -- else (the variant is on chrMT) - - If the allele frequency is above 0.01 in gnomAD-mtDNA global population then this criterion is triggered. - -User Report ------------ - -- The variant frequency. - -Literature ----------- - -- Richards et al. (2015) describes the 5% allele frequency threshold. -- Ghosh et al. (2018) introduce the exception list and ClinGen maintains it. -- McCormick et al. (2020) describe the 1% allele frequency threshold as appropriate for chrMT variants. - -Caveats -------- - -- The exception *"However, there must be no additional conflicting evidence to support pathogenicity, such as a novel occurrence in a certain haplogroup" from McCormick et al. (2020)* is not implemented yet. - -.. _acmg_seqvars_criteria-bs1: - -BS1 (expected frequency) -======================== - -Original Definition -------------------- - - Allele frequency greater than expected for disorder. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- Determine :ref:`acmg_seqvars_criteria-frequency`. -- If the allele frequency is invalid then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the variant is on a nuclear chromosome and the user provided a maximal credible population frequency: - - If the FAF from gnomAD is above the maximal credible population frequency then this criterion is triggered. -- If the variant is on chrMT: - - If the population frequency is above 0.5% then this criterion is triggered in accordance to McCormick et al. (2020). - -User Report ------------ - -- The variant frequency and again the user specified maximal credible population frequency for nuclear variants. -- The variant frequency and the 0.5% threshold for chrMT variants. - -Literature ----------- - -- Richards et al. (2015) describes the original criterion without thresholds. -- Gudmundsson et al. (2022) describe the FAF threshold provided by gnomAD. -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -.. _acmg_seqvars_criteria-bs2: - -BS2 (healthy adult) -=================== - -Original Definition -------------------- - - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the criterion BA1 triggered then this criterion is skipped. -- Determine :ref:`acmg_seqvars_criteria-inheritance` for the gene. -- Determine :ref:`acmg_seqvars_criteria-frequency`. -- If the allele frequency is invalid then this criterion is skipped. -- If the criterion BA1 was triggered then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the gene is marked as recessive or X-linked: - - If the variant allele count is above 2 then this criterion is triggered. -- If the gene is marked as dominant: - - If the variant allele count is above 5 then this criterion is triggered. - -User Report ------------ - -- The variant frequency and the threshold used. - -Literature ----------- - -- Chen et al. (2022), Karczewski et al. (2020), etc. describe gnomAD. -- The modes of inheritance for the genes are taken from different sources as described in :ref:`acmg_seqvars_criteria-inheritance`. - -Caveats -------- - -- The conditions of "full penetrance" and "expected at an early age" need to be checked by the user. - -Notes ------ - -- Genes can be marked as both recessive and dominant. -- We use the thresholds from `PMID:30376034 `__. - -.. _acmg_seqvars_criteria-bs3: - -BS3 (functional studies) -======================== - -No automation has been implemented. - -Original Definition -------------------- - - Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-bs4: - -BS4 (lack of segregation) -========================= - -No automation has been implemented. - -Original Definition -------------------- - - Lack of segregation in affected members of a family - - Caveats: - - - The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. - - Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-bp1: - -BP1 (missense) -============== - -Original Definition -------------------- - - Missense variant in a gene for which primarily truncating variants are known to cause disease - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the criterion BA1 triggered then this criterion is skipped. -- If the variant is on chrMT then this criterion is skipped according to McCormick et al. (2020). -- If the variant is not a missense variant then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the ratio of benign missense variants over all non-VUS missense variants is greater than 0.569 then this criterion is triggered. - -User Report ------------ - -- Report the ratio of benign missense variants over all non-VUS missense variants together with threshold. - -Literature ----------- - -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -Caveats -------- - -- We currently use the threshold from `PMID:30376034 `__ and are lacking our own calibration. - -Notes ------ - -- This criterion is similar to :ref:`acmg_seqvars_criteria-pp2` - -.. _acmg_seqvars_criteria-bp2: - -BP2 (recessive in *trans*) -========================== - -No automation has been implemented. - -Original Definition -------------------- - - Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-bp3: - -BP3 (in-frame repetitive) -========================= - -.. note:: - - - We do not have proper Uniprot data yet (domain / repeat) - - Similar to repeat masker. - - Probably same for phylop100way? - -Original Definition -------------------- - - In-frame deletions/insertions in a repetitive region without a known function. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the criterion BA1 triggered then this criterion is skipped. -- If the variant is on chrMT then this criterion is skipped. - -Implemented Criterion ---------------------- - -- If the variant is in a known functional domain according to UniProt then this criterion is skipped. -- If the variant is in a repeat region according to UniProt repeat annotation genome repeat masker then this criterion is skipped. -- If the variant is in a region of low conservation (PhyloP100Way less than 3.58, same as `PMID:30376034 `__) then this criterion is skipped. -- If all conditions above fail then this criterion is triggered. - -User Report ------------ - -- The variant position and the reason for triggering or skipping. - -Literature ----------- - -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -Caveats -------- - -- We currently use the conservation threshold from `PMID:30376034 `__ and are lacking our own calibration. -- Different from `PMID:30376034 `__, we do not check whether there are known pathogenic variants in the region. - -.. _acmg_seqvars_criteria-bp4: - -BP4 (*in silico* predictions) -============================= - -.. note:: - - - we have not implemented MitoTip or MitImpact yet - - we are lacking phylop scores yet - - we don't have live CADD scores yet - -Original Definition -------------------- - - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). - - Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. - BP4 can be used only once in any evaluation of a variant. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the criterion BA1 triggered then this criterion is skipped. -- If the variant is on chrMT then it is skipped, as we don't have calibration for chrMT yet. -- If the variant is not found in dbNSFP or CADD precomputed scores then it is skipped as we don't have calibration for chrMT yet. - -Implemented Criterion ---------------------- - -See :ref:`acmg_seqvars_criteria-pp3` for details. - -User Report ------------ - -See :ref:`acmg_seqvars_criteria-pp3` for details. - -Literature ----------- - -See :ref:`acmg_seqvars_criteria-pp3` for details. - -Caveats -------- - -See :ref:`acmg_seqvars_criteria-pp3` for details. - -Notes ------ - -- This criterion is similar to :ref:`acmg_seqvars_criteria-pp3` - -.. _acmg_seqvars_criteria-bp5: - -BP5 (found in solved) -===================== - -No automation has been implemented. - -Original Definition -------------------- - - Variant found in a case with an alternate molecular basis for disease. - - -- Richards et al. (2015); Table 4 - -.. _acmg_seqvars_criteria-bp7: - -BP7 (synonymous) -================ - -Original Definition -------------------- - - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. - - -- Richards et al. (2015); Table 4 - -Preconditions / Precomputations -------------------------------- - -- If the variant is on chrMT then this criterion is skipped according to McCormick et al. (2020). - -Implemented Criterion ---------------------- - -- If there is a pathogenic variant +/- 2bp of the position in ClinVar then the criterion is skipped. -- If the variant is closer than 2bp to a splice site then the criterion is skipped. -- If the variant is not predicted to alter the splice site using SpliceAI then the criterion is triggered. - -User Report ------------ - -- The variant position and the reason for triggering or skipping. - -Literature ----------- - -- McCormick et al. (2020) describe the ACMG criteria for chrMT variants. - -Caveats -------- - -N/A - -Notes ------ - -- We use the thresholds from `PMID:30376034 `__. diff --git a/docs/acmg_seqvars_details.rst b/docs/acmg_seqvars_details.rst deleted file mode 100644 index d2712699..00000000 --- a/docs/acmg_seqvars_details.rst +++ /dev/null @@ -1,616 +0,0 @@ -.. _acmg_seqvars_details: - -============================= -AMCG Sequence Variant Details -============================= - -This section describes additional details on our implementation of ACMG classification for sequence variants. - -.. _acmg_seqvars_details-Datas: - ----- -Data ----- - -The following datasources are used in the classification of sequence variants. - -.. list-table:: Tools and datasources used - - * - Data - - Tool / Datasource - - Original Datasource - * - Transcripts - - `Mehari `__ / `cdot `__ - - RefSeq / ENSEMBL - * - Variant Effect Predictions - - `Mehari `__ - - N/A - * - Variant Frequencies - - annonars - - gnomAD exomes, genomes, mtDNA - * - chrMT scores, annotations - - annonars - - MITOMAP, MitoTip, MitImpact, MtSNPscore - * - gene annotations - - annonars - - ClinGen, GCD, gene2phenotype, GenCC, PanelApp, DOMINO - * - protein annotations: domains, repeats, mutations - - UCSC genome browser - - UniProt - -.. _acmg_seqvars_details-references: - ----------- -References ----------- - -Literature with direct ACMG / ACGS / ClinGen relationship - -- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. - *Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.* - Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753. -- ClinGen Sequence Variant Interpretation Work Group. - *Recommendations for ACMG/AMP guideline criteria code modifications nomenclature.* - November 10, 2017. -- Whiffin N, Minikel E, Walsh R, O'Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JS. - *Using high-resolution variant frequencies to empower clinical genome interpretation.* - Genet Med. 2017 Oct;19(10):1151-1158. doi: 10.1038/gim.2017.26. Epub 2017 May 18. PMID: 28518168; PMCID: PMC5563454. -- Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, Harrison SM; ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI). - *Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.* - Hum Mutat. 2018 Nov;39(11):1517-1524. doi: 10.1002/humu.23626. Epub 2018 Sep 7. PMID: 30192042; PMCID: PMC6185798. -- Biesecker LG, Harrison SM; ClinGen Sequence Variant Interpretation Working Group. - *The ACMG/AMP reputable source criteria for the interpretation of sequence variants.* - Genet Med. 2018 Dec;20(12):1687-1688. doi: 10.1038/gim.2018.42. PMID: 29543229; PMCID: PMC6709533. -- Ghosh R, Harrison SM, Rehm HL, Plon SE, Biesecker LG; ClinGen Sequence Variant Interpretation Working Group. - *Updated recommendation for the benign stand-alone ACMG/AMP criterion.* - Hum Mutat. 2018 Nov;39(11):1525-1530. doi: 10.1002/humu.23642. PMID: 30311383; PMCID: PMC6188666. -- ClinGen Sequence Variant Interpretation Work Group. - *SVI Recommendation for in trans Criterion (PM3) - Version 1.0* - 2019. -- Brnich SE, Abou Tayoun AN, Couch FJ, Cutting GR, Greenblatt MS, Heinen CD, Kanavy DM, Luo X, McNulty SM, Starita LM, Tavtigian SV, Wright MW, Harrison SM, Biesecker LG, Berg JS; Clinical Genome Resource Sequence Variant Interpretation Working Group. - *Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.* - Genome Med. 2019 Dec 31;12(1):3. doi: 10.1186/s13073-019-0690-2. PMID: 31892348; PMCID: PMC6938631. -- Ellard S, Baple EL, Berry I, Forrester N, Turnbull C, Owens M, Eccles D, Abbs S, Scott R, Deans Z. - *ACGS best practice guidelines for variant classification 2019.* - 2019. -- ClinGen Sequence Variant Interpretation Work Group. - *SVI Recommendation for Absence/Rarity (PM2) - Version 1.0* - 2020. -- Ellard S, Baple EL, Callaway A, Berry I, Forrester N, Turnbull C, Owens M, Eccles DM, Abbs S, Scott R, Deans ZC, Lester T, Campbell J, Newman WG, Ramsden S, McMullan DJ. - *ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020.* - 2020. -- McCormick EM, Lott MT, Dulik MC, Shen L, Attimonelli M, Vitale O, Karaa A, Bai R, Pineda-Alvarez DE, Singh LN, Stanley CM, Wong S, Bhardwaj A, Merkurjev D, Mao R, Sondheimer N, Zhang S, Procaccio V, Wallace DC, Gai X, Falk MJ. - *Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.* - Hum Mutat. 2020 Dec;41(12):2028-2057. doi: 10.1002/humu.24107. Epub 2020 Nov 10. PMID: 32906214; PMCID: PMC7717623. -- Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. - *Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines.* - Hum Mutat. 2020 Oct;41(10):1734-1737. doi: 10.1002/humu.24088. Epub 2020 Aug 30. PMID: 32720330; PMCID: PMC8011844. -- ClinGen Sequence Variant Interpretation Work Group. - *SVI Recommendation for De Novo Criteria (PS2 & PM6) - Version 1.1* - 2021. -- DiStefano MT, Goehringer S, Babb L, Alkuraya FS, Amberger J, Amin M, Austin-Tse C, Balzotti M, Berg JS, Birney E, Bocchini C. - *The gene curation coalition: a global effort to harmonize gene-disease evidence resources.* - Genetics in Medicine. 2022 Aug 1;24(8):1732-42. -- Pejaver V, Byrne AB, Feng BJ, Pagel KA, Mooney SD, Karchin R, O'Donnell-Luria A, Harrison SM, Tavtigian SV, Greenblatt MS, Biesecker LG, Radivojac P, Brenner SE; ClinGen Sequence Variant Interpretation Working Group. - *Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.* - Am J Hum Genet. 2022 Dec 1;109(12):2163-2177. doi: 10.1016/j.ajhg.2022.10.013. Epub 2022 Nov 21. PMID: 36413997; PMCID: PMC9748256. -- Walker LC, Hoya M, Wiggins GAR, Lindy A, Vincent LM, Parsons MT, Canson DM, Bis-Brewer D, Cass A, Tchourbanov A, Zimmermann H, Byrne AB, Pesaran T, Karam R, Harrison SM, Spurdle AB; ClinGen Sequence Variant Interpretation Working Group. - *Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup.* - Am J Hum Genet. 2023 Jul 6;110(7):1046-1067. doi: 10.1016/j.ajhg.2023.06.002. Epub 2023 Jun 22. PMID: 37352859; PMCID: PMC10357475. - -We currently exclude the following resources (we plan to later incorporate them): - -- Variant Curation Expert Panel (VCEP) Criteria Specifications approved by the SVI VCEP Review Committee -- Strande NT, Riggs ER, Buchanan AH, Ceyhan-Birsoy O, DiStefano M, Dwight SS, Goldstein J, Ghosh R, Seifert BA, Sneddon TP, Wright MW, Milko LV, Cherry JM, Giovanni MA, Murray MF, O'Daniel JM, Ramos EM, Santani AB, Scott AF, Plon SE, Rehm HL, Martin CL, Berg JS. - *Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.* - Am J Hum Genet. 2017 Jun 1;100(6):895-906. doi: 10.1016/j.ajhg.2017.04.015. Epub 2017 May 25. PMID: 28552198; PMCID: PMC5473734. - -Further Supporting Literature - -- Eilbeck K, Lewis SE, Mungall CJ, Yandell M, Stein L, Durbin R, Ashburner M. - The Sequence Ontology: a tool for the unification of genome annotations. - Genome Biol. 2005;6(5):R44. doi: 10.1186/gb-2005-6-5-r44. Epub 2005 Apr 29. PMID: 15892872; PMCID: PMC1175956. -- Quinodoz M, Royer-Bertrand B, Cisarova K, Di Gioia SA, Superti-Furga A, Rivolta C. - *DOMINO: using machine learning to predict genes associated with dominant disorders.* - The American Journal of Human Genetics. 2017 Oct 5;101(4):623-9. -- Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Aguilera MA, Meyer R, Massouras A. - *VarSome: the human genomic variant search engine.* - Bioinformatics. 2019 Jun 6;35(11):1978. -- Martin AR, Williams E, Foulger RE, Leigh S, Daugherty LC, Niblock O, Leong IU, Smith KR, Gerasimenko O, Haraldsdottir E, Thomas E. - *PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels.* - Nature genetics. 2019 Nov;51(11):1560-5. -- Thormann A, Halachev M, McLaren W, Moore DJ, Svinti V, Campbell A, Kerr SM, Tischkowitz M, Hunt SE, Dunlop MG, Hurles ME. - *Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nature communications.* - 2019 May 30;10(1):2373. -- Gudmundsson S, Singer-Berk M, Watts NA, Phu W, Goodrich JK, Solomonson M; Genome Aggregation Database Consortium; Rehm HL, MacArthur DG, O'Donnell-Luria A. - *Variant interpretation using population databases: Lessons from gnomAD.* - Hum Mutat. 2022 Aug;43(8):1012-1030. doi: 10.1002/humu.24309. Epub 2021 Dec 16. PMID: 34859531; PMCID: PMC9160216. - -.. _acmg_seqvars_details-criteria: - --------- -Criteria --------- - -The text in the following section is based on the one by Richards et al. (2015) and the updates listed in :ref:`acmg_seqvars_details-references`. - -.. _acmg_seqvars_details-criteria-pvs: - -Pathogenic Very Strong -====================== - -PVS1 (null variant) -------------------- - -- variant is a null variant (sequence ontology: ``stop_gained``, ``frameshift_variant``, ``splice_acceptor_variant``, ``splice_donor_variant``, ``start_lost``, ``exon_loss_variant``, ``transcript_variant``) -- loss of function is a known disease mechanism for the affected -- incorporate figures 4-5 from Walker et al. (2023) - -**Caveats** - -- beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7) -- caution when interpreting LOF at the extreme 3' and of gene -- caution with splice variants predicted to lead to exon skipping but leave the remainder of the protein intact -- caution in the presence of multiple transcripts - - -PVS1 Update 2018 -~~~~~~~~~~~~~~~~ - -**Decision Tree** - -In Tayoun et al. (2018), the following decision tree is defined. -It is based on the assumption that the gene-disease association is at a moderate, strong, or definitive clinical level according to Strande et al. (2017). -Note that we do not incorporate the matching by Strande et al. (2017) for now. - -1. ``stop_gained`` or ``frameshift_variant`` - 1. predicted to undergo NMD - 1. exon is present in biologically-relevant transcripts - - result: ``PVS1`` - 2. exon is absent from biologically-relevant transcripts - - result: N/A - 2. not predicted to undergo NMD - 1. truncated / altered region is critical to protein function - - result: ``PVS_Strong`` - 2. role of region in protein function is unknown - 1. LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcripts - - result: N/A - 2. LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcripts - 1. variant removes >=10% of the protein - - result: ``PVS_Strong`` - 2. variant removes <10% of the protein - - result: ``PVS1_Moderate`` -2. ``splice_acceptor_variant`` or ``splice_donor_variant`` - 1. exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD - 1. exon is present in biologically-relevant transcripts - - result: ``PVS1`` - 2. exon is absent from biologically-relevant transcripts - - result: N/A - 2. exon skipping or use of a cryptic splice site disrupts reading frame and is **NOT** predicted to undergo NMD - 1. truncated / altered region is critical to protein function - - result: ``PVS_Strong`` - 2. role of region in protein function is unknown - 1. LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcripts - - result: N/A - 2. LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcripts - 1. variant removes >=10% of the protein - - result: ``PVS_Strong`` - 2. variant removes <10% of the protein - - result: ``PVS1_Moderate`` - 3. exon skipping or use of a cryptic splice site rpeserves reading frame - 1. role of region in protein is unknown - 1. LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcripts - - result: N/A - 2. LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcripts - 1. variant removes >=10% of the protein - - result: ``PVS_Strong`` - 2. variant removes <10% of the protein - - result: ``PVS1_Moderate`` - 2. truncated / altered region is critical to protein function - - result: ``PVS_Strong`` -3. ``exon_loss_variant`` or ``transcript_variant`` (single exon or whole transcript deletion) - 1. full gene deletion - - result: ``PVS1`` - 2. single to multi exon deletion - disrupts reading frame and is predicted to undergo NMD - 1. exon is present in biologically-relevant transcripts - - result: ``PVS1`` - 2. exon is absent from biologically-relevant transcripts - - result: N/A - 3. single to multi exon deletion - disrupts reading frame and is **NOT** predicted to undergo NMD - 1. truncated/altered region is critical to protein function - - result: ``PVS_Strong`` - 2. role of region in protein function is unknown - 1. LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcripts - - result: N/A - 2. LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcripts - 1. variant removes >=10% of the eprotein - - result: ``PVS_Strong`` - 2. variant removes <10% of the protein - - result: ``PVS1_Moderate`` - 4. single to multi exon deletion - preserves reading frame - 1. role of region in protein function is unknown -- see 3.3.2 - 2. truncated / altered region is critical to protein function - - result: ``PVS_Strong`` -4. duplication (>=1 exon in size and must be contained within gene) - 1. proven in tandem - 1. reading frame disrupted and NMD predicted to occur - - result: ``PVS1`` - 2. no or unknown impact on reading frame and NMD - - result: N/! - 2. presumed in tandem - 1. reading frame presumed disrupted and NMD predicted to occur - - result: ``PVS1`` - 2. no or unknown impact on reading frame and NMD - - result: N/A - 3. proven not in tandem - - result: N/A -5. ``start_lost`` - 1. no known alternative start codon in other transcripts - 1. >=1 pathogenic variant(s) upstream of closest potential in-frame start codon - - result: ``PVS1_Moderate`` - 2. no pathogenic variant(s) upstream of closest potential in-frame start codon - - result: ``PVS1_Supp`` - 2. different functional transcript uses alternative start codon - - result: N/A - -And here is the tree as an image: - -.. image:: img/Tayoun-2018-Figure-1.png - :alt: Figure 1 from Tayoun et al. (2018) - -**Notes** - -- criterion (2) ``splice_acceptor_variant`` or ``splice_donor_variant`` is mutually exclusive to splice site prediction -- "Generally, NMD is not predicted to occur if the premature termination codon occurs in the 3' most exon or within the 3' most 50 nucleotides of the penultimate exon" -- from Tayoun et al. (2018) - -**Criteria for LoF Disease Mechanism** - -Further, Tayoun et al. (2018) define the following criteria for a loss-of-function disease mechanism. - -1. Follow PVS1 decision tree if: - - clinical validaity classification of gene is strong or definite AND - - >=3 LoF functions are Pathogenic without PVS1 AND - - >10% of variants associated with the phenotype are LoF (must be across more than 1 exon - except for single-exon genes) -2. Decrease final strenght by **one** level (IOW: to ``PVS1_Strong``) if: - - clinical validity classification of gene is at least moderate AND - - >=2 LoF variants have previously associated with the phenotype (must be across more than one exon - except for single-exon genes) AND - - null mouse model recapitulates disease phenotype -3. Decrease final strength by **two** levels (IOW: to ``PVS1_Moderate``) if: - - clinical validity classification of gene is at least moderate AND EITHER - - >=2 LoF variants have been previously associated with the phenotype (must be across more than one exon - except for single-exon genes) OR - - null mouse model recapitulates disease phenotype -4. If there is no evidence that LoF variants cause disease, PVS1 should not be applied at any strength level. - -Pathogenic Strong -================= - -PS1 (same amino acid change) ----------------------------- - -- same amino acid change has previoulsy been established as pathogenic, regardless of nucleotide change -- for splicing variants, Tables 2-3 from Walker et al. (2023) shall be used - -**Table 2 Rules** from Walker et al. (2023) of Variant under assessment (VUA) - -- VUA located outside splice donor / acceptor +/- 1/2 dinucleotide positions - - baseline computational code: PP3 - - position of comparison variant relative to VUA: same nucleotide - - with P comparison variant: PS1 - - with LP comparison variant: PS1_Moderate - - position of comparison variant relative to VUA: within same splice donor / acceptor motif (including +/- 1/2 position) - - with P comparison variant: PS1_Moderate - - with LP comparison variant: PS1_Supporting -- VUA located at splice donor / acceptor +/- 1/2 dinucleotide positions - - baseline computational code: PVS1 - - position of comparison variant relative to VUA: within same splice donor / acceptor +/- 1/2 dinicleotide - - with P comparison variant: VUA is PS1_Supporting - - with LP comparison variant: N/A - - baseline computational code: PVS1 - - position of comparison variant relative to VUA: within same splice donor / acceptor region but outside +/- 1/2 dinicleotide - - with P comparison variant: VUA is PS1_Supporting - - with LP comparison variant: VUA is PS1_Supporting - - baseline computational code: PVS1_Strong, PVS1_Moderate, PVS1_Supporting - - position of comparison variant relative to VUA: within same splice donor / acceptor +/- 1/2 dinicleotide - - with P comparison variant: VUA is PS1 - - with LP comparison variant: VUA is N/A - - baseline computational code: PVS1_Strong, PVS1_Moderate, PVS1_Supporting - - position of comparison variant relative to VUA: within same splice donor / acceptor motify but outside +/- 1/2 dinicleotide - - with P comparison variant: VUA is PS1_Moderate - - with LP comparison variant: VUA is PS1_Supporting - -.. image:: img/Walker-2023-Table-3-1.png - :alt: Table 3 (part 1) from Walker et al. (2023) - -.. image:: img/Walker-2023-Table-3-2.png - :alt: Table 3 (part 2) from Walker et al. (2023) - -.. image:: img/Walker-2023-Table-2.png - :alt: Table 2 from Walker et al. (2023) - -**Caveats** - -- beware of changes that impact splicing rather than amino acid or protein level - -**Notes** - -- incorporation of splicing here is based on the recommendation by Walker et al. (2023) - -PS2 (confirmed *de novo*) -------------------------- - -- confirmed *de novo* variant in a patient withou disease and no family history - -**Caveats** - -- confirmation of paternity only is insufficient (egg donation, surrogate motherhood, errors in embryo transfer, ... can contribute to nonmaternity) - -**Notes** - -- ClinGen Sequence Variant Interpretation Work Group (2021) describe a point-scale for PS2 and PM6. - However, this is hard to apply automatically as it requires an assessment of whether the phenotype is highly specific or consistent with the gene. - -PS3 (functional studies) ------------------------- - -- well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product - -**Caveats** - -- functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established - -**Notes** - -- There is further guidance in Brnich et al. (2020) on how to apply PS3 and BS3 when interpreting "well-established" functional assays. -- However, as this process is manual, it is not further considered here. -- Walker et al. (2023) is not considered here as the authors recommend to capture experimental evidence with PVS1 and is not suitable for automatic classification. - -PS4 (prevalence) ----------------- - -- prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls - -**Caveats** - -- relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. - See Richards et al. (2015) for detailed guidance. -- in instances of very rare variants where case–control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. - -Pathogenic Moderate -=================== - -PM1 (hotspot) -------------- - -- located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation - -**Caveats** - -- Pejaver et al. (2022) suggest to limit combined evidence from P1 and PP3 to strong - -PM3 (recessive and in trans) ----------------------------- - -- for recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient - -According to ClinGen Sequence Variant Interpretation Work Group (2019), there are points awarded per in *trans* proband (all variants should be sufficiently rare, thus meet PM specifiacation, P-Pathogenic or LP-Likely pathogenic): - -.. list-table:: Points per proband - - * - Classification / zygosity of other variant - - Points per confirmed in *trans* - - Points if phase unknown - * - Pathogenic or Likely pathogenic variant - - 1.0 - - 0.5(P) or 0.25(LP) - * - Homozygous occurence (max point 1.0) - - 0.5 - - N/A - * - Uncertain significance variant - - 0.25 - - 0.0 - -The resulting point rating gives the following evidence strength for PM3: - -- 0.5-1.0: PM3_Supporting -- 1.0-2.0: PM3 -- 2.0-4.0: PM3_Strong -- >=4.0: PM3_VeryStrong - -**Notes** - -- ClinGen Sequence Variant Interpretation Work Group (2019) changes this from "for recessive disorders, detected in trans with a pathogenic" to "for recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient" -- Further, this document introduces the point-based system from above. -- There are further considerations in ClinGen Sequence Variant Interpretation Work Group (2019) that are not considered here. - -PM4 (protein length) --------------------- - -- protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - -PM5 (overlapping missense) --------------------------- - -- novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before - -**Caveats** - -- beware of changes that impact splicing rather than at the amino acid/protein level. - - -PM6 (assumed *de novo*) ------------------------ - -- assumed de novo, but without confirmation of paternity and maternity - -Pathogenic Supporting -===================== - -PM2_Supporting (absent from controls) -------------------------------------- - -- absent from controls (or at extremely low frequency if recessive) in gnomAD - -**Notes** - -- population indel data is of high quality by now -- ClinGen Sequence Variant Interpretation Work Group (2020) has downgraded this to PM2_Supporting by default. - -PP1 (cosegregaton) ------------------- - -- cosegregation with disease in multiple affected family members in a gene definitively known to cause th disease - -**Notes** - -- may be used as stronger evidence with increasing segregation data - -PP2 (missense) --------------- - -- missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - -PP3 (*in silico* predictions) ------------------------------ - -- multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) -- incorporate figures 4-5 from Walker et al. (2023) - -.. image:: img/Walker-2023-Figure-5.png - :alt: Figure 5 from Walker et al. (2023) - -**Caveats** - -- because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. - PP3 can be used only once in any evaluation of a variant. -- Pejaver et al. (2022) suggest to limit combined evidence from P1 and PP3 to strong. - -**Notes** - -- The resulting class is updated according to the Pejaver et al. (2022). - Note that it would be very useful to run the original code by Pejaver with more scores. - The code from Pejaver `can be found here on GitHub `__. - -PP4 (monogenetic) ------------------ - -- patient's phenotype or family history is highly specific for a disease with a single genetic etiology - -PP5 (reputable source) ----------------------- - -*Remove according to Biesecker et al. (2018).* - -Benign Standalone -================= - -BA1 (5% frequency) ------------------- - -- allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium - -In accordance with Ghosh et al. (2018), there is a list of exceptions from this rule with high MAF but **some** evidence for pathogenicity. -Updates to this list are available at `ClinGen `__ and shall be monitored regularly. - -- ``NM_014049.4(ACAD):c.-44_-41dupTAAG`` -- ``NM_004004.5(GJB2):c.109G>A (p.Val37Ile)`` -- ``NM_000410.3(HFE):c.187C>G (p.His63Asp)`` -- ``NM_000410.3(HFE):c.845G>A (p.Cys282Tyr)`` -- ``NM_000243.2(MEFV):c.1105C>T (p.Pro369Ser)`` -- ``NM_000243.2(MEFV):c.1223G>A (p.Arg408Gln)`` -- ``NM_006346.2(PIBF1):c.1214G>A (p.Arg405Gln)`` -- ``NM_000017.3(ACADS):c.511C>T (p.Arg171Trp)`` -- ``NM_000060.4(BTD):c.1330G>C (p.Asp444His)`` - -Benign Very Strong -================== - -This category does not exist in Richards et al. (2015) but is implicitely introduced by Tavtigian et al. (2020). - -Benign Strong -============= - -BS1 (expected frequency) ------------------------- - -- allele frequency is greater than expected for disorder - -BS2 (healthy adult) -------------------- - -- observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age - -BS3 (functional studies) ------------------------- - -- well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing - -**Notes** - -- There is further guidance in Brnich et al. (2020) on how to apply PS3 and BS3 when interpreting "well-established" functional assays. - However, as this process is manual, it is not further considered here. -- Walker et al. (2023) is not considered here as the authors recommend to capture experimental evidence with PVS1 and is not suitable for automatic classification. - -BS4 (lack of segregation) -------------------------- - -- lack of segregation in affected members of a family - -**Caveat** - -- presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals -- families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation - -Benign Moderate -=============== - -This category does not exist in Richards et al. (2015) but is implicitely introduced by Tavtigian et al. (2020). - -Benign Supporting -================= - -BP1 (missense) --------------- - -- missense variant in a gene for which primarily truncating variants are known to cause disease - -BP2 (in trans) --------------- - -- Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern - -BP3 (in-frame in repetitive) ----------------------------- - -- in-frame deletions/insertions in a repetitive region without a known function - -BP4 (*in silico* predictions) ------------------------------ - -- multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) -- incorporate figures 4-5 from Walker et al. (2023) - -**Caveats** - -- because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. - -**Notes** - -- The resulting class is updated according to the Pejaver et al. (2022). - Note that it would be very useful to run the original code by Pejaver with more scores. - The code from Pejaver `can be found here on GitHub `__. - -BP5 (found in solved) ---------------------- - -- variant found in a case with an alternate molecular basis for disease - -BP6 (reputable source) ----------------------- - -*Remove according to Biesecker et al. (2018).* - -BP7 (synonymous) ----------------- - -- synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved -- incorporate figures 4-5 from Walker et al. (2023) diff --git a/docs/conf.py b/docs/conf.py index cfc38977..c491863c 100644 --- a/docs/conf.py +++ b/docs/conf.py @@ -36,3 +36,9 @@ # https://sphinxcontrib-bibtex.readthedocs.io/en/latest/usage.html bibtex_bibfiles = ["refs.bib"] + +# -- Special LaTeX Errors ---------------------------------------------------- +# cf. https://stackoverflow.com/a/28454426/84349 +latex_elements = { + "preamble": r"\usepackage{enumitem}\setlistdepth{99}", +} diff --git a/docs/doc_manual.rst b/docs/doc_manual.rst index 95a0b3ca..a7907a19 100644 --- a/docs/doc_manual.rst +++ b/docs/doc_manual.rst @@ -306,3 +306,5 @@ Genome Browser This card provides an internal genome browser with useful tracks for interpreting the variant. You see the genomic location of the variant along with useful tracks from UCSC (e.g. Repeat Masker), RefSeq Genes as well as gnomAD and DGV SVs, ExAC CNVs. + +.. footbibliography:: diff --git a/docs/img/Tayoun-2018-Figure-1.png b/docs/img/Tayoun-2018-Figure-1.png deleted file mode 100644 index 8f575d6c96169d5ebfedefcc0128a6006a3968d3..0000000000000000000000000000000000000000 GIT binary patch literal 0 HcmV?d00001 literal 1590847 zcmZs@2Rzs9{y+XHg_KbdnP~`7R>&-+VH7fwkYrQJmQ|6AP!TF4*<_D0voj*AjBHY5 zXJ!4K@B5td9smFLJRaxV_o+`l@Aq}RuGj0iu6$H3o};E>rXrC@)ECa5Q6rJ4Xh@_T zf|TU=l_ra1ZTw@4jobxwO8m!#^5$a_X&>prnN#YHuYdPAT%p(Mrs(G=K9Jb)I5?4; zPEq|gKkwtjD;WoWXc!*b`9$|ZGxv)tH~fmvD4+D{ke};P-OTIjtE+k{HTn-t{qlPM ztGUUn?80o12Qwei>+6kvG=vMg+W+Vr{V7n*M9Jw%C-;B+&#dYf{webR^SAKv;k7p( zPyJtijQG6+G5WpK`~LG|W0^!Pnd~RJGS-NiY4_&~XB+a{8FlG@gSf`aS*r_Pal9S+{-;h8lSbsT!s@uHuU$| zxhjMQwn?b-mj*9i(4Ksjm&-R6noglo{9P>}R83FgRotZTp%Vd$1;@6H#Ij!+>*5u? zohkYv=a$BNqC{G3ofM1s!>iQt!EY2{hplUubIK)@on~sCrZt(CUm`K5#fK% 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