Variant classification summary

NM_203407.3:c.741A>T

EZHIP · NP_981952.1:p.(Pro247=) · NM_203407.3

GRCh37: chrX:51150609 A>T · GRCh38: chrX:51407757 A>T

Gene: EZHIP Transcript: NM_203407.3

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP7 supporting benign

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Pro247=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_203407.3:c.741A>T is a synonymous variant (Pro247=) in EZHIP, encoding EZH Inhibitory Protein. No CSPEC or VCEP framework exists for this gene; generic ACMG/AMP 2015 criteria are applied.

2

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2 at supporting strength, discounted for synonymous variant with no predicted functional impact).

3

Multiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splice alteration (max delta 0.02), and the variant is synonymous, preserving the amino acid sequence (BP4, supporting benign).

4

The variant satisfies BP7 criteria as a synonymous variant with no predicted splice impact per SpliceAI (supporting benign).

5

Overall, one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP4, BP7) are met. The evidence is balanced, resulting in a classification of Variant of Uncertain Significance (VUS).

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	NM_203407.3:c.741A>T is a synonymous variant (NP_981952.1:p.(Pro247=)) with no predicted null effect on protein function. It does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus variants) per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	This is a synonymous variant with no amino acid change. PS1 requires a known pathogenic missense change at the same codon, which is inapplicable to synonymous variants.
PS2	Not met	No de novo observations have been reported for NM_203407.3:c.741A>T in any available data source.
PS3	Not met	No functional studies have been identified for NM_203407.3:c.741A>T. No variant-specific or systematic-range functional data exists for this synonymous variant.
PS4	Not met	No case-control or statistical evidence supports enrichment of this variant in affected individuals. The variant is absent from ClinVar and has not been reported in any disease cohort.	clinvar
PS5	N/A	This variant is absent from ClinVar; no classification by an expert panel or multiple submitters exists to satisfy PS5.	clinvar
PM1	Not met	NM_203407.3:c.741A>T (Pro247=) is not located within a statistically significant mutational hotspot per cancerhotspots.org, and no critical functional domain has been characterized at this specific residue position for EZHIP.
PM2	Met	NM_203407.3:c.741A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant. However, as a synonymous variant with no predicted splice or functional impact, the absence from population databases provides limited evidence of pathogenicity; applied at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No missense comparator variant exists at the same residue. NM_203407.3:c.741A>T is synonymous (Pro247=) and does not produce an amino acid change; PM5 semantics require alternative missense changes at the same position, which are not applicable.
PM6	Not met	No de novo observation has been reported for NM_203407.3:c.741A>T.
PP1	Not met	No segregation data is available for NM_203407.3:c.741A>T.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. NM_203407.3:c.741A>T is a synonymous variant and does not qualify.
PP3	Not met	Multiple in silico tools do not predict a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.02, well below the 0.2 threshold). REVEL and BayesDel scores are not available for this variant. Available computational evidence does not support a pathogenic role.	spliceai
PP4	Not met	No phenotype specificity data is available for NM_203407.3:c.741A>T. The variant has not been reported in any clinical cohort with a defined phenotype.
PP5	N/A	NM_203407.3:c.741A>T is absent from ClinVar; no reputable source has classified this variant as pathogenic. No 3-star expert panel classification exists.	clinvar
BA1	Not met	NM_203407.3:c.741A>T is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). The BA1 threshold of >1% in population databases is not met.	gnomad_v2 gnomad_v4
BS1	Not met	NM_203407.3:c.741A>T is absent from gnomAD (AF = 0). The BS1 threshold of >0.3% allele frequency in population databases is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous adult observations or unaffected carrier data have been reported for NM_203407.3:c.741A>T.
BS3	Not met	No functional studies have been performed demonstrating that NM_203407.3:c.741A>T has no deleterious effect. No well-established in vitro or in vivo assays exist for this variant.
BS4	Not met	No segregation data is available to evaluate lack of cosegregation with disease for NM_203407.3:c.741A>T.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. NM_203407.3:c.741A>T is a synonymous variant and does not meet the missense requirement.
BP2	Not met	No observation of NM_203407.3:c.741A>T in trans with a pathogenic variant has been reported.
BP3	N/A	Skipped per case instructions — trivially not applicable (in-frame indels in repetitive regions).
BP4	Met	Multiple lines of computational evidence suggest NM_203407.3:c.741A>T has no impact on the gene product. SpliceAI predicts no significant splice impact (max delta score = 0.02, well below the standard 0.2 threshold). The variant is synonymous, predicted to preserve the amino acid sequence (Pro247=). No in silico tool predicts a deleterious effect.	spliceai
BP5	Not met	No case has been identified in which NM_203407.3:c.741A>T is found alongside an alternate molecular basis for disease.
BP6	N/A	NM_203407.3:c.741A>T is absent from ClinVar; no reputable source has classified this variant as benign. No 3-star expert panel classification exists.	clinvar
BP7	Met	NM_203407.3:c.741A>T is a synonymous variant (Pro247=) for which SpliceAI predicts no impact on the splice consensus sequence nor creation of a new splice site (max delta score = 0.02, acceptor gain DS_AG = 0.02, all other deltas = 0.0). Conservation data is unavailable but does not contradict BP7 application.	spliceai

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