NM_203407.3:c.1308C>G

EZHIP · NP_981952.1:p.(Asn436Lys) · NM_203407.3

GRCh37: chrX:51151176 C>G · GRCh38: chrX:51408324 C>G

Gene: EZHIP Transcript: NM_203407.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting benign

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Asn436Lys)

gnomAD AF

0.000693617663895708 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_203407.3:c.1308C>G (p.Asn436Lys) in EZHIP is classified as Benign based on ACMG/AMP 2015 criteria.

BA1 (stand-alone benign): Allele frequency exceeds 1% in gnomAD v4.1, with East Asian subpopulation AF of 1.182% (363/30706 alleles) and 3 homozygous individuals observed. grpmax FAF is 1.082%. This population frequency is incompatible with a highly penetrant Mendelian disease variant.

BP4 (supporting benign): Computational predictors are concordant for a benign interpretation. SpliceAI predicts no splicing alteration (max delta=0.01). BayesDel score is -0.940757, strongly predicting benign effect.

BA1 alone is sufficient for a Benign classification under ACMG/AMP 2015 combination rules. BS1 (strong benign, AF >0.3%) and BP4 (supporting benign, in silico) provide additional supporting evidence.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	Missense variant (c.1308C>G, p.Asn436Lys); does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No prior established pathogenic variant at the same amino acid position (p.Asn436) is documented. ClinVar is absent for this variant; no literature identifies a pathogenic N436 substitution.	clinvar
PS2	Not met	No de novo occurrence data available for this variant. Literature pass identified 0 PMIDs; no family-based or parent-of-origin evidence present.
PS3	Not met	No functional studies identified for NM_203407.3:c.1308C>G or a systematically characterized range that includes position p.Asn436. Literature pass found 0 PMIDs; OncoKB reports unknown oncogenic effect without variant-specific functional data.	oncokb
PS4	Not met	No case-control or prevalence data comparing affected versus general population for this variant. No affected cohort data available.
PS5	Not met	No experimental evidence for a different amino acid change at the same position (p.Asn436) producing a pathogenic effect. No literature or ClinVar data identifies an alternative pathogenic substitution at this residue.	clinvar
PM1	Not met	Residue p.Asn436 is not located in a statistically significant mutational hotspot per cancerhotspots.org. While EZHIP is a functionally characterized PRC2 inhibitory protein, no domain-level evidence maps residue N436 to a critical functional domain from the available data, and no CSPEC/VCEP framework defines domain boundaries for this gene.	oncokb
PM2	Not met	This variant is present in gnomAD at frequencies exceeding the 0.1% PM2 threshold. gnomAD v2.1: 53/183411 alleles (AF=0.029%), grpmax FAF=0.211%; gnomAD v4.1: 395/569478 alleles (AF=0.069%), grpmax FAF=1.082%. The grpmax FAF in both versions exceeds 0.1%, precluding PM2 application.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue pathogenic comparator variants identified in ClinVar. PM5 candidate search returned 0 candidates at residue p.Asn436. Classic same-residue PM5 semantics could not be confirmed.	pm5_candidates clinvar
PM6	Not met	No confirmed de novo occurrence data available. Literature pass identified 0 PMIDs; no parent-of-origin testing or de novo confirmation reported.
PP1	Not met	No cosegregation data available. No family studies or linkage analysis reported for this variant.
PP2	Not met	Without gene-specific metrics or a CSPEC/VCEP framework defining a low benign missense rate for EZHIP, PP2 cannot be reliably applied under generic ACMG/AMP rules. HCI prior score is not available for this gene.
PP3	Not met	Computational evidence does not support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.01). BayesDel score is -0.940757, strongly benign (threshold ≤ -0.36). REVEL is not available for this variant. In silico predictors favor a benign interpretation.	spliceai bayesdel
PP4	Not met	No clinical phenotype data provided in the case files. Without patient phenotype specificity information, PP4 cannot be applied.
PP5	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as pathogenic.	clinvar
BA1	Met	Allele frequency exceeds 1% in gnomAD v4.1. East Asian subpopulation AF is 1.182% (363/30706 alleles) with 3 homozygous individuals. grpmax FAF is 1.082%. On chromosome X, the observation of 3 homozygotes in a general population database provides strong evidence that this is a benign polymorphism rather than a disease-causing variant.	gnomad_v4
BS1	Met	Allele frequency exceeds 0.3% in gnomAD. gnomAD v4.1 grpmax FAF is 1.082% and EAS subpopulation AF is 1.182%, both well above the 0.3% BS1 threshold. This criterion is independently met but is encompassed by the stronger BA1 finding.	gnomad_v4
BS2	Not met	While the variant is observed in population controls at frequencies exceeding 1%, BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No specific disease-penetrance context or healthy control confirmation data is available.
BS3	Not met	No well-established functional studies demonstrate no damaging effect on gene product for this variant. BayesDel benign prediction is computational (BP4 territory), not functional evidence.
BS4	Not met	No segregation data available. No family studies demonstrating lack of cosegregation with disease.
BP1	Not met	No evidence that disease in EZHIP is caused exclusively by an alternative truncating mechanism such that missense variants are unlikely to be pathogenic. BP1 requires a gene where only truncating variants cause disease.
BP2	N/A	No data on in trans observation with a pathogenic variant in a recessive disorder. EZHIP is on chromosome X and no recessive inheritance model has been established for this gene.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing alteration (max delta score=0.01). BayesDel score is -0.940757, strongly predicting a benign effect (threshold ≤ -0.36). REVEL is not available but the available predictors are concordant for a benign interpretation.	spliceai bayesdel
BP5	Not met	No alternative molecular basis for disease has been documented in this case. BP5 requires a specific alternative cause to be identified.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign.	clinvar
BP7	N/A	Synonymous variant criterion. NM_203407.3:c.1308C>G is a missense variant (p.Asn436Lys), not a synonymous or intronic variant.

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