NM_001412.4:c.44G>T (p.Gly15Val) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).1 The p.Gly15Val residue maps to a statistically significant mutational hotspot (PM1_supporting). Multiple in silico predictors suggest no damaging effect: SpliceAI delta 0.01 and BayesDel -0.06 are both consistent with a neutral effect (BP4_supporting_benign).2 One moderate and one supporting pathogenic criterion are countered by one supporting benign criterion. The overall evidence does not meet the threshold for likely pathogenic (requires ≥2 moderate, or 1 moderate + ≥2 supporting) or likely benign (requires ≥2 supporting benign). The variant is classified as a Variant of Uncertain Significance per generic ACMG/AMP 2015 combination rules.3
EIF1AX
Final classification
VUS
PM1PM2BP4
EIF1AX
c.44G>T
p.Gly15Val
This variant
NM_001412.4:c.44G>T (p.Gly15Val) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2
BP4
VUS
EIF1AX c.44G>T
PM1 + PM2 + BP4
→
VUS
Gene diagram
· NM_001412.4 · variants mapped to exon structure
EIF1AX
NM_001412.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 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
✓
PM1
supporting
Pathogenic
The p.Gly15Val residue maps to a statistically significant mutational hotspot as identified by cancerhotspots.org, and is located in the N-terminal region of EIF1AX where recurrent somatic mutations cluster.
Residue at codon 15 is in a statistically significant hotspot per cancerhotspots.org.
✓
PM2
moderate
Pathogenic
NM_001412.4:c.44G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. EIF1AX is located on the X chromosome, further supporting that absence in population databases is significant.
Absent from gnomAD v2.1 (0 alleles)gnomAD v4.1 (0 alleles)gnomAD-Canada v1.0 (0 alleles). Allele frequency effectively 0%.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no damaging effect. SpliceAI predicts no splicing impact (max delta score 0.01). BayesDel score of -0.06 falls in the neutral/benign range. Two independent in silico predictors agree on a neutral effect.
SpliceAI max delta 0.01 (no splice impact). BayesDel -0.0606099 (neutral/benign range).
Assessed · not applied
· 20 not met · 0 not assessed
Pathogenic
PS1
No evidence of a different nucleotide change at the same codon producing the same G15V missense alteration that has been classified as pathogenic.
PS2
No de novo observation with confirmed parentage has been reported for this variant.
PS3
PMID:30305285 is a functional study of EIF1AX in thyroid cancer but does not mention NM_001412.4:c.44G>T (p.Gly15Val) specifically.
PS4
No case-control data or statistically significant enrichment in affected individuals versus controls is available.
PM5
No pathogenic missense variant at the same amino acid residue (Gly15) has been identified in ClinVar.
PM6
No de novo observation, with or without confirmed parentage, has been reported for this variant.
PP1
No cosegregation data in affected family members is available.
PP2
No missense constraint data (HCI prior) is available for EIF1AX.
PP3
Multiple in silico tools predict a neutral effect.
PP4
No patient phenotype or family history information is available to assess specificity for EIF1AX-related disease.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
NM_001412.4:c.44G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from gnomAD population databases; allele frequency is below the 0.3% BS1 threshold.
BS2
No evidence of healthy adult hemizygous or heterozygous carriers has been reported.
BS3
No well-established functional studies demonstrate no damaging effect for NM_001412.4:c.44G>T specifically.
BS4
No segregation data in affected family members is available to assess lack of cosegregation.
BP1
While loss-of-function is supported as a disease mechanism for EIF1AX, the known pathogenic variants in EIF1AX-associated uveal melanoma and thyroid cancer are predominantly missense hotspot mutations.
BP2
No phase data (in cis or in trans with a pathogenic variant) is available.
BP5
No case has been reported in which an alternate molecular basis for disease was identified.
BP6
No reputable source has reported this variant as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
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 = 0.01). BayesDel score = -0.0606099.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63309316, n = 3 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
30305285 ↗
EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.
ONCOKB