Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_004456.4 | RefSeq Select | 2723 nt | 194–2449 |
| NM_004456.3 | Alternative | 2695 nt | 167–2422 |
| NM_004456.5 | MANE Select | 2654 nt | 136–2391 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (5 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The EZH2 D185H variant has not been functionally characterized, and its biological significance remains unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 68 bp |
| Donor Loss (DL) | 0.0 | -72 bp |
| Acceptor Gain (AG) | 0.0 | -19 bp |
| Donor Gain (DG) | 0.0 | 265 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, PVS1 is for null variants in a gene where loss of function is a known disease mechanism. The evidence for this variant shows it is a missense change (D185H) with no predicted null effect. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 is for the same amino acid change as a known pathogenic variant via a different nucleotide change. There is no known pathogenic D185H in EZH2 reported. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence. No parental testing data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 requires well-established functional studies supportive of a damaging effect. No functional studies have been performed for D185H. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals compared to controls. No case-control or affected individual data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 is for variants in mutational hotspots or well-established functional domains. D185 is not documented as a hotspot or critical domain residue. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to standard ACMG guidelines, PM2 requires absence or extremely low frequency in controls. The variant has a MAF of 7.65% in gnomAD with 1,062 homozygotes. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to recessive disorders when detected in trans with a pathogenic variant. No trans data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 is for protein length changes due to in-frame indels or stop‐loss variants. D185H is a missense change with no length alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 is for novel missense changes at residues with other known pathogenic missense variants. No other pathogenic change at D185 is reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo assumption data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 requires co-segregation with disease in multiple affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign variation and where missense is a common disease mechanism. EZH2 has known pathogenic missense variants but also common benign variation. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 requires multiple lines of computational evidence supporting deleterious effect. In silico predictors are predominantly benign and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 is for a highly specific patient phenotype. No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 requires a reputable source reporting pathogenicity. ClinVar reports this variant as benign. Therefore, this criterion is not applied.
BA1 (Stand Alone)
According to standard ACMG guidelines, BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows a MAF of 7.65% in gnomAD with 1,062 homozygotes. Therefore, this criterion is applied at Stand Alone strength because allele frequency far exceeds any threshold for pathogenicity.
BS1 (Not Applied)
According to standard ACMG guidelines, BS1 is: 'Allele frequency is greater than expected for the disorder'. BA1 already covers the stand-alone frequency rule; BS1 is not separately applied to avoid double counting.
BS2 (Strong)
According to standard ACMG guidelines, BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows multiple homozygotes in gnomAD, indicating presence in healthy individuals. Therefore, this criterion is applied at Strong strength.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 requires well-established functional studies showing no damaging effect. No such functional studies exist for D185H. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires lack of segregation in affected family members. No family segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only loss-of-function causes disease. EZH2 pathogenic mechanism includes gain-of-function missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder. No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. In silico tools (CADD, MetaSVM, MetaLR, PrimateAI, REVEL=0.45) and SpliceAI predict no impact. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such case data are provided. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. ClinVar lists this variant as Benign from five clinical labs. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous variants with no splicing impact. This is a missense variant. Therefore, this criterion is not applied.