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. 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).1 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).2 The variant satisfies BP7 criteria as a synonymous variant with no predicted splice impact per SpliceAI (supporting benign).3 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).4
EZHIP
Final classification
Likely Benign
EZHIP c.741A>T · p.Pro247=
EZHIP
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign, BP7 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP7
Likely Benign
EZHIP c.741A>T
PM2 + BP4 + BP7
→
Likely Benign
Gene diagram
· NM_203407.3 · variants mapped to exon structure
EZHIP
NM_203407.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (AF=0).Absent from gnomAD v4.1 (AF=0).Absent from gnomAD-Canada v1.0 (AF=0).
✓
BP4
supporting
Benign
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 max delta = 0.02 (no predicted splice alteration).Synonymous variant (Pro247=) predicted to preserve protein sequence.No REVEL or BayesDel score to suggest deleteriousness.
✓
BP7
supporting
Benign
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.
Synonymous variant with no amino acid change (Pro247=).SpliceAI max delta = 0.02no predicted splice site creation or disruption.
Assessed · not applied
Pathogenic
PS2
No de novo observations have been reported for NM_203407.3:c.741A>T in any available data source.
PS3
No functional studies have been identified for NM_203407.3:c.741A>T.
PS4
No case-control or statistical evidence supports enrichment of this variant in affected individuals.
PM1
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.
PM6
No de novo observation has been reported for NM_203407.3:c.741A>T.
PP1
No segregation data is available for NM_203407.3:c.741A>T.
PP3
Multiple in silico tools do not predict a deleterious effect.
PP4
No phenotype specificity data is available for NM_203407.3:c.741A>T.
Benign
BA1
NM_203407.3:c.741A>T is absent from gnomAD v2.1 and v4.1 (allele frequency = 0).
BS1
NM_203407.3:c.741A>T is absent from gnomAD (AF = 0).
BS2
No homozygous adult observations or unaffected carrier data have been reported for NM_203407.3:c.741A>T.
BS3
No functional studies have been performed demonstrating that NM_203407.3:c.741A>T has no deleterious effect.
BS4
No segregation data is available to evaluate lack of cosegregation with disease for NM_203407.3:c.741A>T.
BP2
No observation of NM_203407.3:c.741A>T in trans with a pathogenic variant has been reported.
BP5
No case has been identified in which NM_203407.3:c.741A>T is found alongside an alternate molecular basis for disease.
N/A · 8
PVS1 · PS1 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links