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""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The EZH2 E148Nfs*2 variant is a truncating mutation that is functionally characterized as likely loss-of-function. Truncating mutations in EZH2 are associated with oncogenic effects, as they can lead to the production of C-terminally truncated proteins. These mutations have been implicated in myelodysplastic syndromes and are known to result in defective differentiation of hematopoietic stem cells. Additionally, patients with EZH2 truncating mutations often exhibit biallelic mutation or loss of heterozygosity at the EZH2 locus, supporting the damaging effect of this variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 86 bp |
| Donor Loss (DL) | 0.03 | -34 bp |
| Acceptor Gain (AG) | 0.0 | 392 bp |
| Donor Gain (DG) | 0.06 | 371 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: c.442_455delinsAACTAATAAAAA causes a frameshift resulting in a premature stop codon (E148Nfs*2) and EZH2 haploinsufficiency is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a LoF gene.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change." The evidence for this variant shows: no previously reported pathogenic variant at amino acid E148. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no data on de novo status. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: functional studies demonstrate that E148Nfs*2 produces a truncated EZH2 protein with loss of function, impaired hematopoietic differentiation, and is associated with oncogenic effects. Therefore, this criterion is applied at Strong strength because multiple well-established studies support a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation." The evidence for this variant shows: no evidence of a mutational hotspot or specific functional domain at E148. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows: not present in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: no data on phase or trans configuration. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a frameshift truncating variant, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before." The evidence for this variant shows: this is a frameshift variant, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of maternity and paternity." The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: this is a frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: no computational predictions indicating deleterious effect (splice predictions low, but frameshift overrides). Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: phenotype data not provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence." The evidence for this variant shows: not present in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age." The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss of function causes disease." The evidence for this variant shows: variant is LOF, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant." The evidence for this variant shows: no phase information. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift, not in-frame. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: the variant causes a frameshift leading to truncation; computational splice predictions are low but do not mitigate loss of function. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence." The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing." The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.