data/acmg_variant_classification_matrix.json

{
  "title": "ACMG / AMP Diagnostic Variant Pathogenicity Classification Table",
  "description": "Formal ACMG/AMP tiering of prioritized candidate variants in proband EX2312012 across MVA and pediatric cancer loci.",
  "variants": [
    {
      "gene": "TRIP13",
      "hgvsc": "c.1060G>A (p.Gly354Ser)",
      "genomic_coord": "chr5:895,302",
      "ref_alt": "G \u2192 A",
      "variant_type": "Missense SNV",
      "vaf": "28.6% (Mosaic Somatic)",
      "acmg_criteria": "PS3 (In vitro SAC silencing disruption), PM1 (AAA+ Walker B motif), PM2 (Absent in gnomAD), PP3 (REVEL=0.88, CADD=28.4)",
      "gnomad_af": "0.000000 (0 / 1.6M alleles)",
      "revel_cadd": "REVEL: 0.88 | CADD: 28.4",
      "acmg_class": "Pathogenic (Mosaic Driver)"
    },
    {
      "gene": "BUB1B",
      "hgvsc": "c.1972C>T (p.Arg658Ter)",
      "genomic_coord": "chr15:40,205,811",
      "ref_alt": "C \u2192 T",
      "variant_type": "Nonsense (Stop Gain)",
      "vaf": "50.0% (Heterozygous)",
      "acmg_criteria": "PVS1 (Nonsense mediated decay before kinase domain), PM2 (Extremely rare in gnomAD), PP3 (CADD=38.0)",
      "gnomad_af": "0.000003 (PopMax: 0.000007)",
      "revel_cadd": "REVEL: N/A | CADD: 38.0",
      "acmg_class": "Pathogenic (MVA1 Susceptibility)"
    },
    {
      "gene": "CEP57",
      "hgvsc": "c.403C>T (p.Arg135Ter)",
      "genomic_coord": "chr11:96,158,214",
      "ref_alt": "C \u2192 T",
      "variant_type": "Nonsense (Premature Stop)",
      "vaf": "50.0% (Heterozygous)",
      "acmg_criteria": "PVS1 (Truncates microtubule-binding domain), PM2 (gnomAD AF < 1e-5), PP4 (Patient matches MVA2 nephrocalcinosis)",
      "gnomad_af": "0.000008 (1 / 125k alleles)",
      "revel_cadd": "REVEL: N/A | CADD: 36.0",
      "acmg_class": "Pathogenic (MVA2 Candidate)"
    },
    {
      "gene": "MAD1L1",
      "hgvsc": "c.1852C>T (p.Arg618Trp)",
      "genomic_coord": "chr7:1,842,504",
      "ref_alt": "C \u2192 T",
      "variant_type": "Missense SNV",
      "vaf": "22.4% (Mosaic Somatic)",
      "acmg_criteria": "PM1 (MAD2-binding dimerization domain), PM2 (Rare in gnomAD), PP3 (AlphaMissense=0.91, CADD=26.2)",
      "gnomad_af": "0.000012 (PopMax: 0.000021)",
      "revel_cadd": "REVEL: 0.79 | CADD: 26.2",
      "acmg_class": "Likely Pathogenic (CIN Modifier)"
    },
    {
      "gene": "CEP192",
      "hgvsc": "c.1504G>A (p.Ala502Thr)",
      "genomic_coord": "chr18:12,874,103",
      "ref_alt": "G \u2192 A",
      "variant_type": "Missense SNV",
      "vaf": "48.2% (Heterozygous)",
      "acmg_criteria": "PM1 (AURKA binding domain), PM2 (gnomAD AF=0.00003), PP3 (REVEL=0.74, CADD=24.1)",
      "gnomad_af": "0.000034 (4 / 118k alleles)",
      "revel_cadd": "REVEL: 0.74 | CADD: 24.1",
      "acmg_class": "Variant of Uncertain Significance (VUS)"
    },
    {
      "gene": "TP53",
      "hgvsc": "c.524G>A (p.Arg175His)",
      "genomic_coord": "chr17:7,675,088",
      "ref_alt": "G \u2192 A",
      "variant_type": "Structural Hotspot Missense",
      "vaf": "18.5% (Mosaic Somatic)",
      "acmg_criteria": "PS1 (Known pathogenic hotspot), PS3 (Loss of transactivation in functional assays), PM1 (DNA-binding domain), PP3 (CADD=32.0)",
      "gnomad_af": "0.000000 (Somatic Hotspot)",
      "revel_cadd": "REVEL: 0.96 | CADD: 32.0",
      "acmg_class": "Pathogenic (Somatic Sarcoma Hit)"
    },
    {
      "gene": "WT1",
      "hgvsc": "c.1180C>T (p.Arg394Trp)",
      "genomic_coord": "chr11:32,417,912",
      "ref_alt": "C \u2192 T",
      "variant_type": "Zinc Finger Missense",
      "vaf": "51.2% (Heterozygous)",
      "acmg_criteria": "PS1 (Denys-Drash hotspot), PM1 (Zinc Finger 3 DNA contact), PP3 (REVEL=0.93, CADD=29.6)",
      "gnomad_af": "0.000000 (0 / 1.6M alleles)",
      "revel_cadd": "REVEL: 0.93 | CADD: 29.6",
      "acmg_class": "Pathogenic (Renal Nephrocalcinosis Corroboration)"
    }
  ]
}