qv_set_id: qv_acmg_sf_v3_3_20250828
version: 1.0.0
title: ACMG secondary findings
description: Report pathogenic or likely pathogenic variants in ACMG SF v3.3 genes with inheritance-aware rules and technical QC.
metadata:
  created: '2025-08-28'
  authors: SwitzerlandOmics
  tags: [ACMG, SF, Clinical, QC]
  acmg_sf_version: v3.3
  schema_fields: SYMBOL,Inheritance,sex,genotype,IMPACT,ACMG_CLASS,SVTYPE,CNV_EXON_COUNT,DP,GQ,AB,TTN_PSI

filters:
  region_include: { description: Limit to ACMG SF genes v3.3, logic: keep_if, field: "OVERLAP(targets.acmg_sf.v3_3.bed)", operator: '>=', value: 1 }
  consent_sf:     { description: Patient opted in to receive secondary findings, logic: keep_if, field: consent_sf_return, operator: '==', value: 1 }
  min_dp:         { description: Minimum read depth, logic: keep_if, field: DP, operator: '>=', value: 10 }
  min_gq:         { description: Minimum genotype quality, logic: keep_if, field: GQ, operator: '>=', value: 20 }

_common:
  p_or_lp: &p_or_lp
    any_of:
      - { field: ACMG_CLASS, operator: '==', value: P }
      - { field: ACMG_CLASS, operator: '==', value: LP }
  gt_het_or_hom: &gt_het_or_hom
    any_of:
      - { field: genotype, operator: '==', value: 1 }
      - { field: genotype, operator: '==', value: 2 }

criteria:
  SF_P_or_LP:
    description: Variant classified as pathogenic or likely pathogenic
    all_of:
      - *p_or_lp

  SF_AD:
    description: Autosomal dominant or X linked dominant. One qualifying allele is sufficient.
    all_of:
      - any_of:
          - { field: Inheritance, operator: '==', value: AD }
          - { field: Inheritance, operator: '==', value: XLD }
      - *gt_het_or_hom
      - *p_or_lp

  SF_XL_male:
    description: X linked recessive. Male hemizygous.
    all_of:
      - { field: Inheritance, operator: '==', value: XLR }
      - { field: sex, operator: '==', value: M }
      - { field: genotype, operator: '==', value: 1 }
      - *p_or_lp

  SF_AR_homozygous:
    description: Autosomal recessive. Homozygous P or LP variant.
    all_of:
      - { field: Inheritance, operator: '==', value: AR }
      - { field: genotype, operator: '==', value: 2 }
      - *p_or_lp

  SF_AR_comphet:
    description: Autosomal recessive. Compound heterozygous P or LP variants. Phase check recommended.
    all_of:
      - { field: Inheritance, operator: '==', value: AR }
      - { field: genotype, operator: '==', value: 1 }
      - *p_or_lp
      - group_by:
          keys: [sample, SYMBOL]
          count: { operator: '>=', value: 2 }

  SF_TTN_truncating_psi90:
    description: TTN truncating in exons with high cardiac expression (PSI >= 0.9).
    all_of:
      - { field: SYMBOL, operator: '==', value: TTN }
      - { field: IMPACT, operator: '==', value: HIGH }
      - { field: TTN_PSI, operator: '>=', value: 0.9 }
      - *gt_het_or_hom
      - *p_or_lp

  SF_SV_CNV:
    description: P or LP exon level CNVs in SF genes.
    all_of:
      - any_of:
          - { field: SVTYPE, operator: '==', value: DEL }
          - { field: SVTYPE, operator: '==', value: DUP }
      - { field: CNV_EXON_COUNT, operator: '>=', value: 1 }
      - *p_or_lp

notes:
  - Assumes ACMG_CLASS values P or LP. If not available, add gene specific LoF rules separately.
  - Assumes targets.acmg_sf.v3_3.bed defines the ACMG SF v3.3 gene set.
  - Consent filter is optional. Remove if not applicable.