Classification rationale

PM2 BP4 VUS

EZHIP c.1504G>A

PM2 was met at supporting strength: NM_203407.3:c.1504G>A is present in gnomAD at very low overall frequency (v2.1 AF=0.00724%, v4.1 AF=0.00581%), below the 0.1% threshold.¹ BP4 was met at supporting benign strength: BayesDel score of -0.855 predicts a benign effect and SpliceAI max delta of 0.01 indicates no splicing impact.² With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and neither the pathogenic nor benign thresholds are reached. This variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 classification rules (PMID:25741868).³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 bayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_203407.3 · variants mapped to exon structure

EZHIP NM_203407.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting review Pathogenic

NM_203407.3:c.1504G>A is present in gnomAD at very low overall frequency (v2.1: AF=0.00724%, 13/179,567 alleles; v4.1: AF=0.00581%, 33/568,384 alleles), below the 0.1% PM2 threshold. However, the variant has been observed in multiple alleles across gnomAD releases with one homozygous (or hemizygous on X) individual, and the East Asian subpopulation frequency is at the threshold borderline (v2.1 EAS AF=0.094%; v4.1 EAS AF=0.104%). PM2 is applied at supporting rather than moderate strength given the presence of multiple population alleles. This variant is absent from gnomAD-Canada.

gnomAD v2.1: AF=0.00724% (13/179567 alleles1 homozygote)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no damaging effect. BayesDel score of -0.855 strongly predicts a benign effect, and SpliceAI max delta of 0.01 indicates no splicing impact. These in silico predictions support a benign interpretation at the supporting level.

BayesDel: -0.855 (predicts benign)SpliceAI max delta: 0.01 (no splice impact)

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No ClinVar or literature data are available to determine whether a different nucleotide change producing the same p.Glu502Lys amino acid substitution has been previously established as pathogenic.

PS2 No de novo observations with confirmed maternity and paternity were identified for this variant in the literature or ClinVar.

PS3 No well-established functional studies for NM_203407.3:c.1504G>A (p.Glu502Lys) were identified.

PS4 No case-control or case series data comparing variant prevalence in affected versus unaffected individuals are available.

PM1 This variant does not lie within a statistically significant mutational hotspot (Hotspots analysis: residue not significant, exact variant not listed).

PM6 No de novo observations (with or without confirmed maternity and paternity) were identified for this variant.

PP1 No cosegregation data are available for this variant.

PP2 No missense constraint metrics (e.g., gnomAD Z-score, o/e ratio) are available for EZHIP to determine whether the gene has a low rate of benign missense variation.

PP3 Multiple lines of computational evidence do not support a deleterious effect.

PP4 No patient phenotype or clinical information was provided for this case.

PP5 No reputable source has classified this variant as pathogenic; it is absent from ClinVar and no expert panel review is available.

Benign

BA1 The overall gnomAD allele frequency (v2.1: 0.00724%; v4.1: 0.00581%) is well below the 1% BA1 threshold for a stand-alone benign classification.

BS1 The highest subpopulation allele frequency (gnomAD v4.1 EAS: 0.104%) is well below the 0.3% BS1 threshold.

BS2 Although the variant is observed in gnomAD, no clinical information is available to determine whether any carriers are healthy adults with a disorder for which full penetrance is expected at an early age.

BS3 No well-established functional studies demonstrating no damaging effect are available for this variant.

BS4 No segregation data are available to evaluate lack of cosegregation with disease.

BP1 While EZHIP loss-of-function is supported as a disease mechanism (PVS1 gene context: LOF eligible), there is insufficient evidence to conclude that truncating variants are the only pathogenic variant type to the exclusion of missense changes.

BP2 No data are available on whether this variant has been observed in trans with a pathogenic variant in a gene associated with a recessive disorder.

BP5 No case data are available identifying an alternate molecular cause for disease in an individual carrying this variant.

BP6 No reputable source classifies this variant as benign; it is absent from ClinVar.

N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.80593e-05; MAF= 0.00581%, 33/568384 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.0010415; MAF= 0.10415%, 32/30725 alleles, homozygotes = 1); grpmax FAF= 0.00075747.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.23964e-05; MAF= 0.00724%, 13/179567 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.000943054; MAF= 0.09431%, 13/13785 alleles, homozygotes = 1); grpmax FAF= 0.00055761.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0058% · 33 / 568,384
1 hom · FAF 0.076%

East Asian 32 / 30,725	0.1% 1 hom
South Asian 1 / 44,644	0.0022%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0072% · 13 / 179,567
1 hom · FAF 0.056%

East Asian

13 / 13,785

0.094%

1 hom

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.855456.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EZHIP, a polycomb binding protein, is recurrently altered by rearrangement and mutation in endometrial stromal sarcomas and posterior fossa ependymoma

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?