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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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