de novo only
HZ[E]
• Hot-Zone de novo mutation in an Essential gene. Essential defined as a
reported lethality gene based on the MGI.
1. “MGI.Essential” = 1
2. Function equals: “NON_SYNONYMOUS_CODING” or
“SPLICE_SITE_ACCEPTOR” or “SPLICE_SITE_DONOR” or
“FRAME_SHIFT” or “STOP_GAINED” or “STOP_LOST”
or “START_LOST” or “CODON*”
3. “Polyphen.Humvar.Prediction” = “probably_damaging” or
“NA”
4. At least one of the following four scores is less than 25:
“X0.1.RVIS..EVS.” or “GenicConstraint.EVS.” or
“X0.05._anypopn_RVIS.tile.ExAC.” or
“GenicConstraint_mis.z.tile.ExAC.”
de novo only
HZ[OMIM]
• Hot-Zone de novo mutation in an OMIM disease associated gene.
1. “OMIM.Disease” does not equal “NA”
2. Function equals: “NON_SYNONYMOUS_CODING” or
“SPLICE_SITE_ACCEPTOR” or “SPLICE_SITE_DONOR”
or “FRAME_SHIFT” or “STOP_GAINED” or
“STOP_LOST” or “START_LOST” or “CODON*”
3. “Polyphen.Humvar.Prediction” = “probably_damaging”
or “NA”
4. At least one of the following four scores is less than 25:
“X0.1.RVIS..EVS.”, “GenicConstraint.EVS.”,
“X0.05._anypopn_RVIS.tile.ExAC.”,
“GenicConstraint_mis.z.tile.ExAC.”
de novo only
OEratio(CDD) <15%tile
• Missense de novo mutation identified in a CDD with an
OEratio among the lowest 15%tile.
1. Function equals:
“NON_SYNONYMOUS_CODING”
2. “subRVIS.Domain.OEratio.Percentile” is < 15
ClinGen / Var [LoF]
All 4 genetic
models
• LoF allele found in a ClinGen defined dosage sensitive gene, or
a gene where at least one ClinVar "Pathogenic" loss-offunction allele has been reported.
1. Function equals: “SPLICE_SITE_ACCEPTOR” or
“SPLICE_SITE_DONOR” or “FRAME_SHIFT”
or “STOP_GAINED” or “STOP_LOST” or
“START_LOST”
2. ClinGen = 1 OR one of:
“ClinVar.Pathogenic.Indel.Count” > 0,
“Clinvar.Pathogenic.CNV.Count” > 0,
“ClinVar.Pathogenic.SNV.Splice.Count” > 0,
“ClinVar.Pathogenic.SNV.Nonsense.Count” > 0
LoF depleted / pLI / pREC
All 4 genetic
models
• A LoF de novo allele found in a gene reported to be LoF
depleted (FDR<0.01), or defined as LoF intolerant based on the
ExAC (pLI>0.9). For recessive genotypes, pLI/pREC>0.9
1. Function equals: “SPLICE_SITE_ACCEPTOR” or
“SPLICE_SITE_DONOR” or “FRAME_SHIFT”
or “STOP_GAINED” or “STOP_LOST” or
“START_LOST”
2. For de novo, either: “LoF.pLI.ExAC.” >0.9 OR
“LoF.FDR.ExAC.” <0.01.
3. For recessive models either: “LoF.pLI.ExAC.”
>0.9 OR “LoF.pRec.ExAC.” >0.9.
Tier 2
All 4 genetic
models
• Bioinformatician highlights any Tier 2 variants he/she judges to be
of potential interest.
KnownVar
• Report if one of the following conditions is met:
1. “HGMD.Class” includes “*DM*”
2. “ClinVar.Clinical.Significance” includes
“*Pathogenic*”
3. “ClinVar.pathogenic.indels” is > 0
All 4 genetic
models
OMIM
GC Clinical Fit (H/M/L):
All 4 genetic
models;
including Tier 2
• GC Evaluation of the relevance to phenotype for all qualifying
variants that affect an OMIM disease-associated gene. Includes
Tier2 tabs.
• Across all models (including Tier 2), list any
qualifying gene where “OMIM.Disease” does
not equal “NA”