NM_203407.3:c.551A>G

EZHIP · NP_981952.1:p.(Tyr184Cys) · NM_203407.3

GRCh37: chrX:51150419 A>G · GRCh38: chrX:51407567 A>G

Gene: EZHIP Transcript: NM_203407.3

Final call

VUS

PS3 supporting PM2 supporting BP4 supporting

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Tyr184Cys)

gnomAD AF

5.403623670033124e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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.	pvs1_generic_framework
PS1	Not met	No established pathogenic variant with the same amino acid change (p.Tyr184Cys) is reported in ClinVar or the published literature.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant; no parental testing has been reported.
PS3	Met	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.	PMID:29909548
PS4	Not met	No case-control studies or systematic case series reporting this variant in affected individuals with a germline phenotype are available.
PS5	Not met	This variant is absent from ClinVar; no expert panel or clinical laboratory has classified it as pathogenic.	clinvar
PM1	Not met	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.	PMID:29909548
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo occurrence has been reported for this variant; parental confirmation is absent.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	Not met	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.
PP3	Not met	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.	bayesdel spliceai
PP4	Not met	No clinical data on the patient's phenotype specificity for EZHIP-related disease are available for assessment.
PP5	Not met	This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic.	clinvar
BA1	Not met	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%.	gnomad_v4
BS1	Not met	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%.	gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	PMID:29909548
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease are available for this variant.
BP1	Not met	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.	PMID:29909548
BP2	Not met	No observation of this variant in trans with a known pathogenic EZHIP variant has been reported.
BP4	Met	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.	bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	This variant is absent from ClinVar; no expert panel or reputable source has classified it as benign.	clinvar
BP7	N/A	BP7 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.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; this is a single-nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders; EZHIP is not established as a gene in which biallelic pathogenic variants cause a recessive disorder.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants; this is a missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.