NM_203407.3:c.1272G>A

EZHIP · NP_981952.1:p.(Gln424=) · NM_203407.3

GRCh37: chrX:51151140 G>A · GRCh38: chrX:51408288 G>A

Gene: EZHIP Transcript: NM_203407.3

Final call

Likely Benign

BS1 supporting benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Gln424=)

gnomAD AF

0.0001422547554359757 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_203407.3:c.1272G>A (p.Gln424=) is a synonymous variant in EZHIP exon 1. SpliceAI predicts no splicing impact (max delta=0.02), consistent with a silent substitution.

This variant is present in gnomAD v2.1 with a grpmax filtering allele frequency of 0.47% (82/204,972 alleles, 1 homozygote) and an East Asian subpopulation frequency of 0.54% (80/14,835 alleles, 1 homozygote), exceeding the 0.3% threshold expected for a rare disease variant and supporting a benign interpretation.

The variant is absent from ClinVar and has not been reported in the published literature. No functional studies, segregation data, or case-control evidence exists to support pathogenicity.

No pathogenic criteria are met. Benign evidence includes BS1 (supporting benign; population frequency), BP4 (supporting benign; in silico predictions), and BP7 (supporting benign; synonymous with silent splice prediction). Overall, the variant is classified as Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	N/A	Synonymous variant (NP_981952.1:p.(Gln424=)) does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). ClinGen SVI PVS1 decision tree does not apply.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No pathogenic variant has been reported at this nucleotide position (NM_203407.3:c.1272) in ClinVar or the published literature. No same-site comparator exists.	clinvar
PS2	Not met	No de novo observation has been reported for this variant in any publication or database.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for this variant. OncoKB reports Unknown Oncogenic Effect with no supporting PMIDs.	oncokb
PS4	Not met	No case-control or case series data exist for this variant. The variant is absent from ClinVar and no publications mention it.	clinvar
PS5	Not met	No evidence this variant has been observed in trans with a known pathogenic variant in a recessive disorder.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot or a well-established critical functional domain without benign variation.
PM2	Not met	Although total gnomAD v2.1 allele frequency is 0.04% (below 0.1% threshold), the grpmax filtering allele frequency is 0.47% with 1 homozygote, exceeding the 0.1% rarity threshold. This variant is not sufficiently rare to meet PM2.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant (p.Gln424=) produces no amino acid change. PM5 requires a different pathogenic missense change at the same residue and does not apply to synonymous variants.	pm5_candidates
PM6	Not met	No confirmed de novo observation (with maternity and paternity confirmed) has been reported for this variant.	clinvar
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This variant is synonymous, not missense.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.02). REVEL and BayesDel scores are unavailable for this variant.	spliceai
PP4	Not met	No patient phenotype or clinical data are available for this variant. No case reports exist in the literature.	clinvar
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	No population allele frequency exceeds 1%. Highest subpopulation frequency is East Asian at 0.54% in gnomAD v2.1 (below 1% BA1 threshold).	gnomad_v2 gnomad_v4
BS1	Met	gnomAD v2.1 grpmax filtering allele frequency is 0.47% (East Asian AF 0.54%) with 1 homozygote, exceeding the 0.3% threshold expected for a rare disease variant. gnomAD v4.1 grpmax FAF of 0.19% falls below the threshold, introducing some uncertainty; strength reduced to supporting benign to reflect this discrepancy and the uncertain disease prevalence for EZHIP.	gnomad_v2 gnomad_v4
BS2	Not met	No direct evidence that this variant has been observed in healthy adults for a disorder with full penetrance. EZHIP disease association and penetrance are not well established.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this synonymous variant.	oncokb
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is synonymous, not missense.
BP2	Not met	No evidence of this variant observed in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder.
BP3	N/A	Variant is a substitution, not an in-frame indel. BP3 applies only to in-frame deletions or insertions in non-repeat regions.
BP4	Met	Multiple lines of computational evidence suggest no impact. SpliceAI predicts no splicing effect (max delta=0.02, well below 0.1 threshold). The variant is synonymous (p.Gln424=) with no predicted protein change. REVEL and BayesDel are unavailable but the consistent benign in silico profile supports BP4.	spliceai
BP5	Not met	No evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	Met	Synonymous variant (NP_981952.1:p.(Gln424=)) with SpliceAI max delta score of 0.02, predicting no impact on splicing or creation of a novel splice site. Nucleotide-level conservation data are not available, but the absent splice prediction supports a silent effect.	spliceai

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