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Diagnostic Columns

TRIO/DUO analysis primary columns

  • Single Variant Prioritization: variant prioritization flags which reflected the order of single variants reviewing SOP.
    • 01_TIER1_DNM_HZ: Tier 1 De novo variants in "Hot Zone"
    • 02_TIER1_DNM: Tier 1 De novo non-HZ variants
    • 03_TIER1_HOMO_HEMI: Tier 1 Homo/Hemi variants
    • 04_TIER2_DNM: Tier 2 De novo variants
    • 05_TIER2_HOMO_HEMI: Tier 2 Homo/Hemi variants
    • 06_LOF_GENE: LoF Dominant and Haploinsufficient Gene
    • 07_KNOWN_VAR: Previously reported ClinVar P/LP variants or HGMD DM (as long as it is NOT ClinVar B/LB)
    • 08_CLINVAR_SITE: >=1 ClinVar P/LP variant at site. Includes precise indel overlaps.
    • 09_CLINVAR_2BP: >= 1 ClinVar P/LP variant within 2bp flanking. Includes precise indel overlaps.
    • 10_HGMD_SITE: >=1 HGMD DM variant at site. Includes precise indel overlaps.
    • 11_MIS_HOT_SPOT: Missense Dominant and Haploinsufficient Gene + ClinVar PLP 25bpflanks count >= 6
    • 12_TIER1_OMIM_MIS_INFRAME: High-quality ultra rare novel missense/inframe indel variants
    • 13_ACMG_GENE: ACMG v3 gene associated variants
  • Compound Het Variant Prioritization:
    • 01_TIER1
    • 02_TIER2
  • Denovo Flag (autosome):
    • DE NOVO: Het in proband, high coverage homo ref in both parents
    • POSSIBLY DE NOVO: Het in proband, homozygous ref in both parents where at least one is low coverage
    • NEWLY HOMOZYGOUS: High coverage homozygous in proband, het in both parents (any coverage)
    • UNLIKELY NEWLY HOMOZYGOUS: Homozygous in proband and high coverage homozygous ref in one or both parents UNLESS one parent is high coverage homozygous variant
    • POSSIBLY NEWLY HOMOZYGOUS: Homozygous in proband and Low coverage anything in both parents unless het in both; High coverage het in one parent and low coverage anything in the other; High coverage het in both parents ONLY IF low coverage homo in proband
    • COMPOUND DELETION: One allele is a SNV and the 2nd allele is a deletion
    • NO FLAG: Proband homo variant, one parent high coverage homo variant; Proband het unless both parents are homo non-carriers
  • Denovo Flag (sex chr):
    • NEWLY HEMIZYGOUS: Proband hemizygous variant, mother high coverage het
    • UNLIKELY DE NOVO OR NEWLY HEMIZYGOUS: Proband heterozygous, mother homozygous reference
    • NEWLY HEMIZYGOUS OR POSSIBLE DE NOVO: Proband hemizygous variant, mother low coverage homo ref
    • POSSIBLY NEWLY HEMIZYGOUS: Proband hemizygous variant, mother low coverage het
    • NO FLAG: Male het, mother homo variant
  • Inherited From: Father or Mother or NA
  • Denovo HZ[E]: hot zone de novo mutation found in an essential (mouse lethality based on the MGI) gene
  • ClinGen/Var [LoF]: LoF variant found in a ClinGen defined dosage sensitive gene, or a gene where at least one ClinVar "Pathogenic" loss-of-function allele has been reported
  • LoF depleted/pLI: A protein-truncating predicted de novo allele found in a gene reported to be loss-of-function depleted (FDR<0.01, Petrovski et al.), or defined as LoF intolerant based on the ExAC paper (p>0.9). Restricted to de novo mutations. For recessive genotypes (HEM, HOM, CHET), pLI/pREC>0.9.
  • Compound Var: comphet variants' identifier with #1 refers to 1st var and #2 for 2nd var.
  • Var Ctrl Freq #1 & #2 (co-occurance): co-occurance frequency for comphet within default 10k control cohorts.
  • Tier Flag (Compound Var): Tier 1 or Tier 2 for comphet.
  • Tier Flag (Single Var): Tier 1 or Tier 2 for singleton variants.
  • Pass Tier 2 Inclusion Criteria: indicate whether the variant pass tier 2 inclusion criteria
  • LoF Dominant and Haploinsufficient Gene: LoF variant associated with either ClinGen dominant or OMIM dominant gene
  • Known Pathogenic Variant: either HGMD DM or ClinVar P/LP

Singleton analysis primary columns

  • Single Variant Prioritization: variant prioritization flags which reflected the order of single variants reviewing SOP.
    • 01_LOF_GENE: LoF Dominant and Haploinsufficient Gene
    • 02_TIER1_HOMO_HEMI: Tier 1 Homo/Hemi variants
    • 03_KNOWN_VAR: Previously reported ClinVar P/LP variants or HGMD DM (as long as it is NOT ClinVar B/LB)
    • 04_CLINVAR_SITE: >=1 ClinVar P/LP variant at site. Includes precise indel overlaps.
    • 05_CLINVAR_2BP: >= 1 ClinVar P/LP variant within 2bp flanking. Includes precise indel overlaps.
    • 06_HGMD_SITE: >=1 HGMD DM variant at site. Includes precise indel overlaps.
    • 07_MIS_HOT_SPOT: Missense Dominant and Haploinsufficient Gene + ClinVar PLP 25bpflanks count >= 6
    • 08_TIER1_OMIM_MIS_INFRAME: High-quality ultra rare novel missense/inframe indel variants
    • 09_ACMG_GENE: ACMG v3 gene associated variants
  • Compound Het Variant Prioritization:
    • 01_TIER1
    • 02_TIER2
  • Compound Var: comphet variants' identifier with #1 refers to 1st var and #2 for 2nd var.
  • Var Ctrl Freq #1 & #2 (co-occurance): co-occurance frequency for comphet within default 10k control cohorts.
  • Tier Flag (Compound Var): Tier 1 or Tier 2 for comphet
  • Tier Flag (Single Var): Tier 1 or Tier 2 for singleton variants.
  • Pass Tier 2 Inclusion Criteria: indicate whether the variant pass tier 2 inclusion criteria
  • LoF Dominant and Haploinsufficient Gene: LoF variant associated with either ClinGen dominant or OMIM dominant gene
  • Known Pathogenic Variant: either HGMD DM or ClinVar P/LP