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EZHIPc.1504G>AUncertain significance
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Variant interpretation report

EZHIP c.1504G>A, p.(Glu502Lys)

NM_203407.3:c.1504G>A NP_981952.1:p.(Glu502Lys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About EZHIP

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
33 / 568,384 alleles

gnomAD v4.1: 33 / 568,384 alleles. Recorded AF 5.80593e-05. Recorded homozygote count 1.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 4 not met · 17 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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).

Met · 2

PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.00724% (13/179
  • 567 alleles
  • 1 homozygote)
  • grpmax FAF=0.056%
  • gnomAD v4.1: AF=0.00581% (33/568
  • 384 alleles
  • grpmax FAF=0.076%
  • gnomAD-Canada v1.0: absent
  • Highest subpopulation AF: EAS 0.094% (v2.1) / 0.104% (v4.1)
Still missing
  • EAS subpopulation AF (0.104% in v4.1) slightly exceeds 0.1% PM2 threshold
  • homozygote count on X chromosome warrants careful interpretation.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.855 (predicts benign)
  • SpliceAI max delta: 0.01 (no splice impact)
Still missing
  • REVEL not available
  • no additional in silico predictors evaluated.
Sources
bayesdelspliceai ↗

Not met · 4 · evaluated, threshold not reached

PM1 This variant does not lie within a statistically significant mutational hotspot (Hotspots analysis: residue not significant, exact variant not listed). No evidence of a critical functional domain with established pathogenic missense clustering was identified. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • exact variant not listed in known hotspots.
PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score is -0.855, strongly predicting a benign effect. SpliceAI max delta is 0.01, indicating no splicing impact. REVEL and HCI prior are unavailable for this variant. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.855 (predicts benign)
  • SpliceAI max delta: 0.01 (no splicing impact)
  • REVEL: unavailable (chrX:51408520 not found in REVEL data)
Still missing
  • REVEL score unavailable.
Sources
bayesdelspliceai ↗
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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0.00724% < 1% BA1 threshold.
  • gnomAD v4.1 AF=0.00581% < 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The highest subpopulation allele frequency (gnomAD v4.1 EAS: 0.104%) is well below the 0.3% BS1 threshold. The grpmax filtering allele frequency (v2.1: 0.056%; v4.1: 0.076%) is also below 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 EAS AF=0.094% < 0.3% BS1 threshold
  • gnomAD v4.1 EAS AF=0.104% < 0.3% BS1 threshold
  • grpmax FAF v2.1=0.056%
  • v4.1=0.076%
  • both < 0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 17 · no assessment recorded

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. Details ▾Hide ▴
Still missing
  • No ClinVar submissions for this residue
  • no literature identifying alternate nucleotide changes at Glu502.
PS2 No de novo observations with confirmed maternity and paternity were identified for this variant in the literature or ClinVar. Details ▾Hide ▴
Still missing
  • No de novo reports available.
PS3 No well-established functional studies for NM_203407.3:c.1504G>A (p.Glu502Lys) were identified. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB reports no variant-specific functional evidence
  • classification is Unknown Oncogenic Effect.
Still missing
  • No functional assay data for p.Glu502Lys.
Sources
oncokb ↗
PS4 No case-control or case series data comparing variant prevalence in affected versus unaffected individuals are available. Details ▾Hide ▴
Still missing
  • No case-control studies or case series data.
PM6 No de novo observations (with or without confirmed maternity and paternity) were identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports available.
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation analysis.
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. Details ▾Hide ▴
Still missing
  • No missense constraint data retrieved for EZHIP.
PP4 No patient phenotype or clinical information was provided for this case. Details ▾Hide ▴
Still missing
  • No clinical phenotype or family history available.
PP5 No reputable source has classified this variant as pathogenic; it is absent from ClinVar and no expert panel review is available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no expert panel or reputable source classification.
Still missing
  • No external classification available.
Sources
clinvar ↗
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. Details ▾Hide ▴
Still missing
  • No clinical data on gnomAD carriers.
BS3 No well-established functional studies demonstrating no damaging effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional assay data.
BS4 No segregation data are available to evaluate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No family or segregation data.
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. BP1 cannot be applied without gene-specific data showing that missense variants are not disease-causing. Details ▾Hide ▴
Evidence considered
  • EZHIP LOF mechanism supported but no evidence that missense variants are benign.
Still missing
  • No data establishing that only truncating variants cause EZHIP-related disease.
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. Details ▾Hide ▴
Still missing
  • No trans-observation data.
BP5 No case data are available identifying an alternate molecular cause for disease in an individual carrying this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular cause data available.
BP6 No reputable source classifies this variant as benign; it is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any source.
Still missing
  • No external benign classification available.
Sources
clinvar ↗
PS5 This variant is absent from ClinVar; no expert panel or reputable source classification is available. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no submissions for this variant.
Still missing
  • No ClinVar classification or expert panel review.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_203407.3:c.1504G>A is a missense variant (p.Glu502Lys). The generic PVS1 decision framework (PMC6185798) applies only to null variants (nonsense, frameshift, and canonical ±1,2 splice consensus changes); this variant falls into the 'other' bucket and is not eligible for PVS1. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant eligible for PVS1 under ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders; no recessive disease association has been established for EZHIP in the context of this assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is a missense substitution, not a protein-length-altering variant (stop-loss, start-loss, or in-frame indel); PM4 does not apply. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AAutomated PM5 candidate harvesting was unable to identify same-residue (Glu502) comparator pathogenic variants in ClinVar; PM5 semantics could not be confirmed. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found no Glu502 comparator variants with pathogenic classification.
BP3 N/AVariant is a substitution, not an in-frame deletion or insertion; BP3 applies only to in-frame indels. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_203407.3:c.1504G>A is a missense variant (p.Glu502Lys), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Identifiers

Gene
EZHIP
Transcript
NM_203407.3
Coding (HGVS c.)
NM_203407.3:c.1504G>A
Protein (HGVS p.)
NP_981952.1:p.(Glu502Lys)
GRCh38
chrX:51408520 G>A
GRCh37
chrX:51151372 G>A

Gene diagram

Every interpreted variant in EZHIP, mapped onto the exon structure of NM_203407.3. Select a row to find it on the plot.

EZHIPNM_203407.3
Fetching transcript structure from UCSC…
gnomAD v4.1 33 / 568,384 alleles AF 5.81e-05 · 1 homozygotes · FAF 0.000757
gnomAD v2.1 13 / 179,567 alleles AF 7.24e-05 · 1 homozygotes · FAF 0.000558
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.8e-05 · 33 / 568,384 alleles · 1 hom · FAF 0.00076
East Asian32 / 30,725 0.0011 hom
South Asian1 / 44,644 2.2e-05
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 7.2e-05 · 13 / 179,567 alleles · 1 hom · FAF 0.00056
East Asian13 / 13,785 0.000941 hom
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -47 bp
0.000
SpliceAI acceptor gainat +20 bp
0.000
SpliceAI donor lossat +97 bp
0.000
SpliceAI donor gainat -183 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
-0.855

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.855 (predicts benign)
  • SpliceAI max delta: 0.01 (no splice impact)
Still missing
  • REVEL not available
  • no additional in silico predictors evaluated.
Sources
bayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score is -0.855, strongly predicting a benign effect. SpliceAI max delta is 0.01, indicating no splicing impact. REVEL and HCI prior are unavailable for this variant. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.855 (predicts benign)
  • SpliceAI max delta: 0.01 (no splicing impact)
  • REVEL: unavailable (chrX:51408520 not found in REVEL data)
Still missing
  • REVEL score unavailable.
Sources
bayesdelspliceai ↗
BP7 N/ANM_203407.3:c.1504G>A is a missense variant (p.Glu502Lys), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 33 / 568,384 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

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

Functional

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.