0%
EZHIPc.551A>GUncertain significance
Print report
Variant interpretation report

EZHIP c.551A>G, p.(Tyr184Cys)

NM_203407.3:c.551A>G NP_981952.1:p.(Tyr184Cys) 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: 2 Benign evidence criteria: 1
Pathogenic criteria applied · 2
PS3Supporting
PS3 · supporting

The p.Tyr184Cys variant was directly tested in lentiviral expression assays in NSCs and HEK293 cells and was shown to reduce H3K27me3 levels, consistent with retained EZHIP-mediated PRC2 inhibition. This is a single study in a somatic cancer biology context (PFA ependymoma); the functional effect is clear but the study does not constitute systematic range characterization, and the relevance to germline disease is uncertain.

PM2Supporting
PM2 · supporting

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 6.60×10⁻⁶ (1/151,595 alleles), gnomAD v4.1 AF = 5.40×10⁻⁶ (3/555,183 alleles), and absent from gnomAD-Canada. These frequencies are well below the 0.1% PM2 threshold for a rare variant absent from controls.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no deleterious impact. BayesDel score of −0.923011 strongly predicts a benign effect, and SpliceAI predicts no splicing alteration (max delta score = 0.01). REVEL and HCI prior scores are unavailable.

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: PS3 supporting, PM2 supporting, BP4 supporting; combination = 2 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
3 / 555,183 alleles

gnomAD v4.1: 3 / 555,183 alleles. Recorded AF 5.40362e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.59652e-06; MAF= 0.00066%, 1/151595 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.39509e-05; MAF= 0.00640%, 1/15637 alleles, homozygotes = 0).

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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → 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: 3 met · 22 not met · 0 not assessed · 4 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

NM_203407.3:c.551A>G (p.Tyr184Cys) is a missense variant in EZHIP, a gene encoding a PRC2 inhibitory protein with a described role in posterior fossa group A ependymomas.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 6.60×10⁻⁶ (1/151,595 alleles) and gnomAD v4.1 AF = 5.40×10⁻⁶ (3/555,183 alleles), with no homozygotes observed (PM2_Supporting).

In a functional study of EZHIP/CXorf67 in PFA ependymomas (PMID 29909548), lentiviral expression of the p.Tyr184Cys mutant in neural stem cells and HEK293 cells produced reduction in H3K27me3 levels comparable to wildtype, demonstrating that the variant retains PRC2 inhibitory activity. This constitutes PS3_Supporting in a somatic cancer context; relevance to germline disease is uncertain.

Multiple lines of computational evidence predict a benign effect: BayesDel score of −0.923011 strongly predicts benign, and SpliceAI predicts no splicing impact (max delta = 0.01) (BP4_Supporting).

The variant is absent from ClinVar and has not been classified by any clinical laboratory or expert panel.

The p.Tyr184Cys substitution lies outside the characterized mutational hotspot region of EZHIP (codons 71–122) and is not located at a statistically significant cancer hotspot residue.

Overall, the variant has one pathogenic supporting criterion (PS3_Supporting), one benign supporting criterion (BP4_Supporting), and one population-based supporting criterion (PM2_Supporting). The evidence is insufficient to classify the variant as pathogenic, likely pathogenic, benign, or likely benign; it remains a variant of uncertain significance.

Met · 3

PS3 SupportingThe p.Tyr184Cys variant was directly tested in lentiviral expression assays in NSCs and HEK293 cells and was shown to reduce H3K27me3 levels, consistent with retained EZHIP-mediated PRC2 inhibition. This is a single study in a somatic cancer biology context (PFA ependymoma); the functional effect is clear but the study does not constitute systematic range characterization, and the relevance to germline disease is uncertain. Details ▾Hide ▴
Evidence considered
  • PMID 29909548: Y184C was one of three CXorf67/EZHIP mutant variants (T73S
  • I88F
  • Y184C) tested by lentiviral expression in NSCs and HEK293 cells. All three mutants produced H3K27me3 reduction similar to wildtype CXorf67 overexpression.
  • Y184C lies outside the main hotspot region (codons 71–122) but was directly assayed and demonstrated a functional effect on PRC2 activity.
Still missing
  • Functional data derived from somatic cancer context (PFA ependymoma)
  • germline disease relevance of the observed PRC2 inhibition is not established.
  • Single study
  • no independent replication of the Y184C functional effect.
Sources
PMID:29909548 ↗
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 6.60×10⁻⁶ (1/151,595 alleles), gnomAD v4.1 AF = 5.40×10⁻⁶ (3/555,183 alleles), and absent from gnomAD-Canada. These frequencies are well below the 0.1% PM2 threshold for a rare variant absent from controls. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1 allele in 151
  • 595 (AF = 6.60×10⁻⁶)
  • highest in South Asian (AF = 6.40×10⁻⁵)
  • 0 homozygotes.
  • gnomAD v4.1: 3 alleles in 555
  • 183 (AF = 5.40×10⁻⁶)
  • highest in South Asian (AF = 4.70×10⁻⁵)
  • gnomAD-Canada v1.0: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. BayesDel score of −0.923011 strongly predicts a benign effect, and SpliceAI predicts no splicing alteration (max delta score = 0.01). REVEL and HCI prior scores are unavailable. Details ▾Hide ▴
Evidence considered
  • BayesDel: −0.923011 (strongly benign prediction).
  • SpliceAI: max delta = 0.01 (no splicing impact).
Still missing
  • REVEL score unavailable for chrX.
Sources
bayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PVS1 NM_203407.3:c.551A>G (p.Tyr184Cys) is a missense variant and does not fall into the null-variant categories (nonsense, frameshift, canonical ±1,2 splice consensus variants) required for PVS1 application under the ClinGen SVI PVS1 decision framework. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • variant not eligible for PVS1 null-variant buckets per PMC6185798.
Sources
pvs1_generic_framework ↗
PS1 No established pathogenic variant with the same amino acid change (p.Tyr184Cys) is reported in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid-change comparator exists.
Sources
clinvar ↗
PS2 No de novo occurrence data are available for this variant; no parental testing has been reported. Details ▾Hide ▴
Evidence considered
  • No de novo data in ClinVar or literature.
Still missing
  • Absence of parental testing data.
PS4 No case-control studies or systematic case series reporting this variant in affected individuals with a germline phenotype are available. Details ▾Hide ▴
Evidence considered
  • No published case-control or case-series data for this variant in a germline disease context.
Still missing
  • Absence of case-control or cohort studies.
PM1 The p.Tyr184Cys variant lies outside the characterized mutational hotspot region of EZHIP/CXorf67 (codons 71–122) and is not located in a statistically significant hotspot per cancerhotspots.org. No well-characterized critical functional domain has been defined at this residue position. Details ▾Hide ▴
Evidence considered
  • PMID 29909548: 15 of 22 (68%) CXorf67 mutations cluster in the hotspot region between codons 71–122. Y184C (residue 184) is explicitly noted as 'outside the hotspot region.'
  • Cancerhotspots.org: residue not statistically significant.
Sources
PMID:29909548 ↗
PM5 No pathogenic missense variant at the same amino acid residue (Tyr184) has been identified in ClinVar. Automated PM5 candidate harvesting found no same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants identified in ClinVar or databases.
Sources
pm5_candidates
PM6 No de novo occurrence has been reported for this variant; parental confirmation is absent. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • Absence of parental testing.
PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
  • No co-segregation data with disease in families.
Still missing
  • Absence of family segregation studies.
PP2 EZHIP is not established as a gene in which missense variants are a common mechanism of disease with a low rate of benign missense variation. The gene has a single exon and the characterized pathogenic variants in PFA ependymomas are predominantly somatic, not germline. Details ▾Hide ▴
Evidence considered
  • No ClinGen CSPEC or published evidence establishing EZHIP as a gene where missense variants are a predominant germline disease mechanism.
Still missing
  • Gene-level disease mechanism for germline missense variants is not established.
PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score of −0.923011 strongly predicts a benign effect, and SpliceAI predicts no splicing impact (max delta score = 0.01). REVEL and HCI prior scores are unavailable for this variant. Details ▾Hide ▴
Evidence considered
  • BayesDel score: −0.923011 (strongly benign prediction).
  • SpliceAI max delta: 0.01 (no predicted splicing impact).
  • REVEL: not available for chrX at this position.
Still missing
  • REVEL score unavailable for X chromosome.
Sources
bayesdelspliceai ↗
PP4 No clinical data on the patient's phenotype specificity for EZHIP-related disease are available for assessment. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data provided for PP4 evaluation.
Still missing
  • Patient phenotype information needed to assess PP4.
PP5 This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no classification from any submitter.
Sources
clinvar ↗
BA1 The variant's maximum population frequency (gnomAD v4.1 South Asian AF = 4.70×10⁻⁵, 0.0047%) is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: maximum subpopulation AF = 4.70×10⁻⁵ (South Asian)
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The variant's maximum population frequency (gnomAD v4.1 South Asian AF = 4.70×10⁻⁵, 0.0047%) is far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: maximum subpopulation AF = 4.70×10⁻⁵ (South Asian)
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 No systematic observation of this variant in healthy homozygous or hemizygous adult individuals has been documented. gnomAD reports zero homozygotes and alleles are limited to the XX subpopulation. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1 allele in SAS_XX (female subpopulation)
  • 0 homozygotes
  • 0 hemizygotes in XY populations.
  • gnomAD v4.1: 2 alleles in SAS_XX
  • 1 in NFE_XX
Still missing
  • No data on healthy adult hemizygous males.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 The only functional study available (PMID 29909548) demonstrates that p.Tyr184Cys retains EZHIP-mediated PRC2 inhibitory function, reducing H3K27me3 levels in cellular assays. This does not support a benign effect; the variant shows a functional consequence consistent with the oncogenic mechanism described for EZHIP in PFA ependymomas. Details ▾Hide ▴
Evidence considered
  • PMID 29909548: Y184C mutant produced H3K27me3 reduction comparable to wildtype CXorf67 and other mutants
  • does not demonstrate a benign or neutral functional effect.
Sources
PMID:29909548 ↗
BS4 No segregation data demonstrating lack of co-segregation with disease are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data.
Still missing
  • Absence of segregation analysis.
BP1 There is no evidence that EZHIP-related disease is caused exclusively by truncating variants. Both truncating and missense variants have been observed in PFA ependymomas, and the gene's mechanism remains primarily characterized in a somatic cancer context. Details ▾Hide ▴
Evidence considered
  • PMID 29909548: Of 22 CXorf67 SNVs in PFA ependymomas
  • 68% are missense clustered in codons 71–122
  • no evidence that only truncating variants are pathogenic.
Still missing
  • Germline disease spectrum for EZHIP not well characterized.
Sources
PMID:29909548 ↗
BP2 No observation of this variant in trans with a known pathogenic EZHIP variant has been reported. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available.
Still missing
  • Absence of phase data with known pathogenic variants.
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Evidence considered
  • No cases with alternate molecular cause documented.
BP6 This variant is absent from ClinVar; no expert panel or reputable source has classified it as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any submitter.
Sources
clinvar ↗
PS5 This variant is absent from ClinVar; no expert panel or clinical laboratory has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no classification available.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to recessive disorders; EZHIP is not established as a gene in which biallelic pathogenic variants cause a recessive disorder. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_203407.3:c.551A>G is a missense variant (p.Tyr184Cys), not a synonymous change. Details ▾Hide ▴
Evidence considered
  • Missense substitution (Tyr→Cys)
  • not synonymous.

Identifiers

Gene
EZHIP
Transcript
NM_203407.3
Coding (HGVS c.)
NM_203407.3:c.551A>G
Protein (HGVS p.)
NP_981952.1:p.(Tyr184Cys)
GRCh38
chrX:51407567 A>G
GRCh37
chrX:51150419 A>G

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 3 / 555,183 alleles AF 5.4e-06 · 0 homozygotes · FAF 7.78e-06
gnomAD v2.1 1 / 151,595 alleles AF 6.6e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.4e-06 · 3 / 555,183 alleles · 0 hom · FAF 7.8e-06
South Asian2 / 42,588 4.7e-05
European (non-Finnish)1 / 300,845 3.3e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 6.6e-06 · 1 / 151,595 alleles · 0 hom
South Asian1 / 15,637 6.4e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.40362e-06; MAF= 0.00054%, 3/555183 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.69616e-05; MAF= 0.00470%, 2/42588 alleles, homozygotes = 0); grpmax FAF= 7.78e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.59652e-06; MAF= 0.00066%, 1/151595 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.39509e-05; MAF= 0.00640%, 1/15637 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +127 bp
0.010
SpliceAI acceptor gainat -18 bp
0.010
SpliceAI donor lossat +435 bp
0.000
SpliceAI donor gainat -219 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
-0.923

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. BayesDel score of −0.923011 strongly predicts a benign effect, and SpliceAI predicts no splicing alteration (max delta score = 0.01). REVEL and HCI prior scores are unavailable. Details ▾Hide ▴
Evidence considered
  • BayesDel: −0.923011 (strongly benign prediction).
  • SpliceAI: max delta = 0.01 (no splicing impact).
Still missing
  • REVEL score unavailable for chrX.
Sources
bayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score of −0.923011 strongly predicts a benign effect, and SpliceAI predicts no splicing impact (max delta score = 0.01). REVEL and HCI prior scores are unavailable for this variant. Details ▾Hide ▴
Evidence considered
  • BayesDel score: −0.923011 (strongly benign prediction).
  • SpliceAI max delta: 0.01 (no predicted splicing impact).
  • REVEL: not available for chrX at this position.
Still missing
  • REVEL score unavailable for X chromosome.
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_203407.3:c.551A>G is a missense variant (p.Tyr184Cys), not a synonymous change. Details ▾Hide ▴
Evidence considered
  • Missense substitution (Tyr→Cys)
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.923011.

1 paper record listed. 1 cited in the classification.

Cited in the classification

  • Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.
    The p.Tyr184Cys (Y184C) variant in EZHIP/CXorf67 was identified among 22 somatic SNVs in a cohort of 675 PFA ependymomas. Lentiviral expression of Y184C in NSCs and HEK293 cells produced reduction in H3K27me3 levels comparable to wildtype CXorf67 and hotspot mutants T73S and I88F, demonstrating retained PRC2 inhibitory function. Y184C lies outside the main hotspot region (codons 71–122).
    → PS3 Names this variant
    PMID 29909548 ↗
    Source detail
    Lentiviral infection with constructs containing three mutant variants of CXorf67 produced the same effect on H3 K27-me3. The three mutant variants were SNVs found in our series of PFA ependymomas; two within and one outside the hotspot region (T73S, I88F, Y184C).

    Location Results; Figure 7

    Context Lentiviral expression in neural stem cells (NSCs) and HEK293 cells; H3K27me3 measurement by immunofluorescence and immunoblotting

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

gnomAD v4.1 3 / 555,183 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= 5.40362e-06; MAF= 0.00054%, 3/555183 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.69616e-05; MAF= 0.00470%, 2/42588 alleles, homozygotes = 0); grpmax FAF= 7.78e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.59652e-06; MAF= 0.00066%, 1/151595 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.39509e-05; MAF= 0.00640%, 1/15637 alleles, homozygotes = 0).

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 = -0.923011.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

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.