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.1 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.2 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.3 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.4
EZHIP
Final classification
Likely Benign
BS1BP4BP7
EZHIP
c.1272G>A
p.Gln424=
This variant
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 supporting benign, BP4 supporting benign, BP7 supporting benign; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP4BP7
Likely Benign
EZHIP c.1272G>A
BS1 + 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 · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
Benign
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 v2.1: grpmax FAF=0.47%East Asian AF=0.54%82/204972 alleles
✓
BP4
supporting
Benign
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 max delta=0.02 (no splice impact predicted)Synonymous variant with no amino acid changeREVEL/BayesDel unavailable
✓
BP7
supporting
Benign
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.
Synonymous variant p.(Gln424=)no amino acid changeSpliceAI max delta=0.02 (no splice impact predicted)
Assessed · not applied
· 18 not met · 0 not assessed
Pathogenic
PS1
No pathogenic variant has been reported at this nucleotide position (NM_203407.3:c.1272) in ClinVar or the published literature.
PS2
No de novo observation has been reported for this variant in any publication or database.
PS3
No well-established in vitro or in vivo functional studies have been identified for this variant.
PS4
No case-control or case series data exist for this variant.
PM1
This variant does not lie in a statistically significant mutational hotspot or a well-established critical functional domain without benign variation.
PM2
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.
PM6
No confirmed de novo observation (with maternity and paternity confirmed) has been reported for this variant.
PP1
No segregation data are available for this variant in affected families.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or clinical data are available for this variant.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
No population allele frequency exceeds 1%.
BS2
No direct evidence that this variant has been observed in healthy adults for a disorder with full penetrance.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this synonymous variant.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease in affected families.
BP2
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.
BP5
No evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified.
BP6
No reputable source has classified this variant as benign.
N/A · 5
PVS1 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000142255; MAF= 0.01423%, 81/569401 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00234497; MAF= 0.23450%, 72/30704 alleles, homozygotes = 1); grpmax FAF= 0.00190909.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000400055; MAF= 0.04001%, 82/204972 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00539265; MAF= 0.53927%, 80/14835 alleles, homozygotes = 1); grpmax FAF= 0.00468821.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.000414651002073255, 6/14470 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.014%
· 81 / 569,401
1 hom · FAF 0.19%
1 hom · FAF 0.19%
East Asian 72 / 30,704 |
0.23% 1 hom |
Remaining individuals 7 / 26,445 |
0.026% |
South Asian 1 / 44,788 |
0.0022% |
Admixed American 1 / 45,068 |
0.0022% |
+ 6 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.04%
· 82 / 204,972
1 hom · FAF 0.47%
1 hom · FAF 0.47%
East Asian 80 / 14,835 |
0.54% 1 hom |
Remaining individuals 1 / 5,334 |
0.019% |
South Asian 1 / 19,053 |
0.0052% |
+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))
gnomAD Canada 🇨🇦
0.041%
· 6 / 14,470
0 hom · FAF 0.25%
0 hom · FAF 0.25%
East Asian 6 / 1,040 |
0.58% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)
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