NM_203407.3:c.1504G>A

EZHIP · NP_981952.1:p.(Glu502Lys) · NM_203407.3

GRCh37: chrX:51151372 G>A · GRCh38: chrX:51408520 G>A

Gene: EZHIP Transcript: NM_203407.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Glu502Lys)

gnomAD AF

5.80593401643959e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	N/A	NM_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.	pvs1_generic_framework
PS1	Not assessed	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.
PS2	Not assessed	No de novo observations with confirmed maternity and paternity were identified for this variant in the literature or ClinVar.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	No case-control or case series data comparing variant prevalence in affected versus unaffected individuals are available.
PS5	Not assessed	This variant is absent from ClinVar; no expert panel or reputable source classification is available.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Automated PM5 candidate harvesting was unable to identify same-residue (Glu502) comparator pathogenic variants in ClinVar; PM5 semantics could not be confirmed.
PM6	Not assessed	No de novo observations (with or without confirmed maternity and paternity) were identified for this variant.
PP1	Not assessed	No cosegregation data are available for this variant.
PP2	Not assessed	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.
PP3	Not met	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.	bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical information was provided for this case.
PP5	Not assessed	No reputable source has classified this variant as pathogenic; it is absent from ClinVar and no expert panel review is available.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect are available for this variant.
BS4	Not assessed	No segregation data are available to evaluate lack of cosegregation with disease.
BP1	Not assessed	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.
BP2	Not assessed	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.
BP4	Met	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.	bayesdel spliceai
BP5	Not assessed	No case data are available identifying an alternate molecular cause for disease in an individual carrying this variant.
BP6	Not assessed	No reputable source classifies this variant as benign; it is absent from ClinVar.	clinvar
BP7	N/A	NM_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.
BP3	N/A	Variant is a substitution, not an in-frame deletion or insertion; BP3 applies only to in-frame indels.
PM3	N/A	PM3 applies to recessive disorders; no recessive disease association has been established for EZHIP in the context of this assessment.
PM4	N/A	Variant is a missense substitution, not a protein-length-altering variant (stop-loss, start-loss, or in-frame indel); PM4 does not apply.

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