The variant NM_001412.4:c.25G>C (p.Gly9Arg) lies within the N-terminal tail (NTT) of EIF1AX, a critical functional domain for translation initiation complex stability, satisfying PM1 at moderate strength.1 Functional studies demonstrate that p.Gly9Arg directly increases affinity for EIF5 and elevates nascent protein synthesis, consistent with a gain-of-function effect on the translation pre-initiation complex, supporting PS3 at moderate strength.2 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), supporting PM2 at supporting strength.3 Multiple in silico tools predict a benign effect: SpliceAI delta score is 0.02 (no splicing impact) and BayesDel score is -0.100602 (benign range), supporting BP4 at supporting strength.4 The variant has been reported in somatic cancers (COSMIC, n=4) and is classified as Likely Oncogenic by OncoKB, confirming its oncogenic potential. However, as a germline variant, its clinical significance remains uncertain in the absence of germline case data.5
EIF1AX
Final classification
VUS
EIF1AX c.25G>C · p.Gly9Arg
EIF1AX
The variant NM_001412.4:c.25G>C (p.Gly9Arg) lies within the N-terminal tail (NTT) of EIF1AX, a critical functional domain for translation initiation complex stability, satisfying PM1 at moderate strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, BP4 supporting; combination = 2 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PS3PM1PM2
BP4
VUS
EIF1AX c.25G>C
PS3 + 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 · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
moderate
review
Pathogenic
The variant p.Gly9Arg was directly tested in functional studies. Co-immunoprecipitation experiments demonstrated increased affinity for EIF5 compared to wild-type EIF1AX, indicating stabilization of the translation pre-initiation complex. Expression of G9R in NthyOri thyroid cells increased nascent protein synthesis, consistent with a gain-of-function effect on translation initiation.
PMID:30305285: G9R directly tested — co-IP shows increased EIF5 binding (Fig. 3B)increased nascent protein synthesis in NthyOri cells (Fig. 3D-E).G9R is one of three NTT mutants (G8R
✓
PM1
moderate
Pathogenic
The variant p.Gly9Arg is located within the N-terminal tail (NTT, residues 2–15) of EIF1AX, a well-characterized functional domain critical for translation initiation fidelity and pre-initiation complex stability. Cancerhotspots.org identifies this residue as statistically significant. Multiple cancer types harbor recurrent somatic mutations clustered in this domain.
Cancerhotspots.org: residue is statistically significant.PMID:30305285: NTT domain (residues 2–15) extensively characterized as critical for PIC stability and start codon selectionmutations in this region are lethal in yeast.
✓
PM2
supporting
Pathogenic
The variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), satisfying the PM2 threshold of <0.1% allele frequency under generic ACMG/AMP rules.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no splicing effect (max delta score 0.02). BayesDel score (-0.100602) falls in the benign range below the pathogenic threshold. While REVEL is not available, the concordance of available in silico tools supports a benign interpretation.
SpliceAI: max delta 0.02 — no predicted splicing impact.BayesDel: -0.100602 — below pathogenic threshold.
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with a different amino acid substitution at the same codon (Gly9) is present in ClinVar or the published literature.
PS4
No case-control data or affected vs.
PP1
No co-segregation data is available for this variant.
PP2
HCI prior score is not available for EIF1AX.
PP3
In silico predictors do not support a deleterious effect.
PP4
No patient phenotype or clinical data is available for this variant.
PP5
The variant is absent from ClinVar.
Benign
BA1
The variant is absent from gnomAD; allele frequency does not exceed the 1% threshold required for BA1 (stand-alone benign).
BS1
The variant is absent from gnomAD; allele frequency does not exceed the 0.3% threshold required for BS1.
BS2
No observation of this variant in healthy adults has been reported.
BS3
No well-established functional studies demonstrate a neutral or benign effect.
BS4
No segregation data is available to assess lack of co-segregation with disease.
BP1
EIF1AX missense variants in the N-terminal tail are the predominant variant type associated with oncogenesis; there is no evidence that primarily truncating variants cause disease in this gene.
BP2
No observation of this variant in trans with a known pathogenic variant in a gene associated with recessive disease.
BP5
No evidence that this variant is observed in a case with an alternate molecular basis for disease.
BP6
The variant is absent from ClinVar.
N/A · 5
PVS1 · PS2 · PM5 · PM6 · 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 = 0.02). BayesDel score = -0.100602.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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; COSV63309272, n = 4 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & References.
EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.
Searched
c.25G>Cp.Gly9ArgG9R
Found
EIF1AX-G9R was directly tested in co-immunoprecipitation and protein synthesis assays. G9R, along with G8R and G15V, exhibited increased affinity for EIF5 compared to wild-type EIF1AX, and expression of G9R increased nascent protein synthesis in NthyOri thyroid cells, demonstrating a gain-of-function effect on translation pre-initiation complex stability.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PS3 supports · met
Why
Variant-specific functional data confirmed in somatic/thyroid cancer context; directly referenced in PS3 (moderate) and PM1 (moderate) assessments. Gain-of-function effect demonstrated, though germline disease mechanism alignment requires further clarification.
EIF1AX mutants, particularly G8R, G9R and c'spl, exhibited increased affinity for EIF5
Location Results: 'EIF1AX mutants have higher affinity to components of the translation PIC and increase protein synthesis' (Fig. 3A, 3B, 3D, 3E); Discussion paragraph 1 · Context Co-immunoprecipitation in HEK293T cells; L-azidohomoalanine (AHA) labeling in NthyOri thyroid cells for nascent protein synthesis · full text
Sources & reference links
Triaged references · 1 PMID not cited in assessment
26878173 ↗
Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers.
ONCOKB