ClinVar Variant Classification with ACMG/AMP Terms

# ClinVar variant classification with the ACMG/AMP five terms (training exercise)
#
# THIS IS A TRAINING AND REVIEW EXERCISE, NOT CLINICAL DIAGNOSIS. Nothing here
# is a clinical interpretation, and the cases must not be used for patient care.
# Per the abstract of Richards et al., clinical testing "should be performed in
# a CLIA-approved laboratory with results interpreted by a board-certified
# clinical molecular geneticist or molecular genetic pathologist or equivalent."
#
# Standard:  Richards et al., 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. Genetics in Medicine 17(5),
#            405-424, 2015.
# DOI:       10.1038/gim.2015.30
# PMC:       https://pmc.ncbi.nlm.nih.gov/articles/PMC4544753/
# BibTeX (Crossref):
#   @article{Richards_2015,
#     title     = {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},
#     volume    = {17},
#     ISSN      = {1098-3600},
#     url       = {http://dx.doi.org/10.1038/gim.2015.30},
#     DOI       = {10.1038/gim.2015.30},
#     number    = {5},
#     journal   = {Genetics in Medicine},
#     publisher = {Elsevier BV},
#     author    = {Richards, Sue and Aziz, Nazneen and Bale, Sherri and Bick, David and Das, Soma and Gastier-Foster, Julie and Grody, Wayne W. and Hegde, Madhuri and Lyon, Elaine and Spector, Elaine and Voelkerding, Karl and Rehm, Heidi L.},
#     year      = {2015},
#     month     = May,
#     pages     = {405--424}
#   }
# Archive:   ClinVar. Landrum et al., ClinVar: public archive of interpretations
#            of clinically relevant variants. Nucleic Acids Research 44(D1),
#            D862-D868, 2016. DOI 10.1093/nar/gkv1222
# Data:      https://www.ncbi.nlm.nih.gov/clinvar/
#            The ClinVar track below is read by the browser from NCBI's FTP site
#            (https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar.vcf.gz,
#            with its .tbi index). Nothing from ClinVar is copied into this folder.
# Licence:   NCBI's policies page (https://www.ncbi.nlm.nih.gov/home/about/policies/)
#            says "NCBI itself places no restrictions on the use or distribution
#            of the data contained therein" and adds that "some submitters of the
#            original data" may claim rights. ClinVar's own data-use page returned
#            a bot check and was not read, so the sample items below are
#            illustrative. They are invented cases at invented positions inside
#            real gene spans (Ensembl GRCh38 gene coordinates), with no ClinVar
#            record, variant identifier or classification copied. A position may
#            show a ClinVar record in the track or none.
# Reference: the hg38 genome and its gene annotation are igv.js's built-in genome,
#            fetched from the internet, which is why allow_remote is true.
#
# The five terms (abstract of Richards et al.): 'pathogenic', 'likely
# pathogenic', 'uncertain significance', 'likely benign', and 'benign'.
#
# Evidence criteria. The multiselect lists the 28 criteria codes of Tables 3
# (PVS1, PS1-PS4, PM1-PM6, PP1-PP5) and 4 (BA1, BS1-BS4, BP1-BP7), with the
# wording of each table row. The tables' caveats and notes are left out.
#
# Adaptations (this design differs from the original standard here):
#   - Potato records the criteria an annotator ticks and the verdict they pick.
#     It does NOT apply Table 5, the rules for combining criteria into a
#     classification, and it does not check that the verdict follows from the
#     ticked criteria. The ticked list and the verdict are independent answers.
#   - The standard weights criteria as very strong, strong, moderate,
#     supporting or stand-alone, and a laboratory may adjust a weight. This
#     design records only which criteria are present.
#   - The cases are invented summaries, so no criterion can be confirmed from
#     real patient, family or functional data. The note and the tracks are the
#     only evidence. A real review would use data this design does not carry.
#   - ClinVar review statuses are out of scope. Their wording was not read.
#
# No model_training block. Potato's trainers consume text, images, audio and
# similar data, and none reads a genome locus. This design only collects labels.
#
# Run from this folder:
#   potato start config.yaml -p 8000

annotation_task_name: "ClinVar variant classification (ACMG/AMP training exercise)"
task_dir: "."

data_files:
  - "sample-data.json"

item_properties:
  id_key: id
  text_key: note

output_annotation_dir: "annotation_output"
export_annotation_format: jsonl

instance_display:
  fields:
    - key: note
      type: text
      label: "Illustrative case (not a real patient)"
    - key: locus
      type: genome_locus
      label: "Locus (GRCh38)"
      display_options:
        genome: hg38
        allow_remote: true
        flank: 100
        select_features: true
        tracks:
          - name: "ClinVar (NCBI, GRCh38)"
            url: "https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar.vcf.gz"
            format: vcf

user_config:
  allow_all_users: true

annotation_instructions: |
  This is a training exercise, not a clinical diagnosis. Read the illustrative
  case note, look at the locus in the browser, and classify the variant with
  the five terms of the ACMG/AMP standard (Richards et al., 2015). Then tick
  the evidence criteria you relied on. The criteria are a record of your
  reasoning. Potato does not combine them or check them against your verdict.

annotation_schemes:
  - annotation_type: radio
    name: acmg_classification
    description: "Classify the variant with the ACMG/AMP terms"
    humanize_labels: false
    labels:
      - name: "pathogenic"
        key_value: "1"
      - name: "likely pathogenic"
        key_value: "2"
      - name: "uncertain significance"
        key_value: "3"
      - name: "likely benign"
        key_value: "4"
      - name: "benign"
        key_value: "5"
    label_requirement:
      required: true

  - annotation_type: multiselect
    name: acmg_criteria
    description: "Which ACMG/AMP evidence criteria apply? (select all that apply)"
    humanize_labels: false
    labels:
      - "PVS1: 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"
      - "PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change"
      - "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history"
      - "PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product"
      - "PS4: The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls"
      - "PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation"
      - "PM2: Absent from controls (or at extremely low frequency if recessive) (see Table 6) in Exome Sequencing Project, 1000 Genomes or ExAC"
      - "PM3: For recessive disorders, detected in trans with a pathogenic variant"
      - "PM4: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants"
      - "PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before"
      - "PM6: Assumed de novo, but without confirmation of paternity and maternity"
      - "PP1: Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease"
      - "PP2: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease"
      - "PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc)"
      - "PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology"
      - "PP5: Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation"
      - "BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC"
      - "BS1: Allele frequency is greater than expected for disorder (see table 6)"
      - "BS2: 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: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing"
      - "BS4: Lack of segregation in affected members of a family"
      - "BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease"
      - "BP2: 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 deletions/insertions in a repetitive region without a known function"
      - "BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)"
      - "BP5: Variant found in a case with an alternate molecular basis for disease"
      - "BP6: Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation"
      - "BP7: 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"

  - annotation_type: viewer_selection
    name: evidence_feature
    description: "Evidence (optional): click the ClinVar record or gene you based this on"
    viewer_field: locus
    max_selections: 4