NM_001412.4:c.26G>A

EIF1AX · NP_001403.1:p.(Gly9Asp) · NM_001412.4

GRCh37: chrX:20156731 C>T · GRCh38: chrX:20138613 C>T

Gene: EIF1AX Transcript: NM_001412.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting BP4 supporting benign

Variant details

Gene

EIF1AX

Transcript

NM_001412.4

Protein

NP_001403.1:p.(Gly9Asp)

gnomAD AF

0.0 (v4.1)

ClinVar

Likely oncogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001412.4:c.26G>A (p.Gly9Asp) is a missense variant in exon 2 of EIF1AX, a gene encoding a translation initiation factor in which N-terminal tail (NTT) missense mutations are established oncogenic drivers.

The variant is absent from gnomAD v2.1 and v4.1 (0/1,168,429 alleles), meeting PM2 (supporting).

The p.Gly9 residue lies within the NTT functional domain (residues ~2-15), a well-characterized hotspot for gain-of-function cancer mutations that impair scanning arrest and enhance translation of cell cycle genes. This satisfies PM1 at moderate strength.

Functional characterization by Sehrawat et al. (2019) demonstrated that the G9D/R13H double mutant reduces binding to ribosomal protein Rps10, and other NTT mutants including G9R (same position) enhance translation of long 5'UTR mRNAs. OncoKB independently curates this variant as Likely Oncogenic with Likely Gain-of-function effect. This satisfies PS3 at supporting strength.

In silico predictors favor a neutral effect: BayesDel score is -0.034 (predicted benign) and SpliceAI max delta is 0.02 (no splice impact). This satisfies BP4 (supporting benign).

The overall evidence profile consists of one moderate pathogenic criterion (PM1), two supporting pathogenic criteria (PM2, PS3), and one supporting benign criterion (BP4). Per the generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate plus two supporting criteria does not reach the threshold for Likely Pathogenic (which requires two moderate and two supporting, or three moderate, or one strong and two supporting). The single supporting benign criterion does not independently reach any benign classification threshold. The variant is therefore classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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_001412.4:c.26G>A is a missense variant (p.Gly9Asp). It does not fall into any default PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision framework from PMC6185798 does not apply to this variant class.	pvs1_generic_framework
PS1	Not met	No evidence was identified that a different nucleotide change at c.26 leading to the same p.Gly9Asp amino acid substitution has been classified as pathogenic in a clinical database or the literature. PS1 requires a previously established pathogenic variant producing the same amino acid change via a different nucleotide substitution.
PS2	Not assessed	No de novo data (parental testing results, trio sequencing) is available for this variant. PS2 cannot be assessed without confirmed de novo observation.
PS3	Met	Functional characterization of the EIF1AX N-terminal tail (NTT) domain, where p.Gly9Asp resides, was performed by Sehrawat et al. (PMID:30420357). The G9D/R13H double mutant showed reduced binding to ribosomal protein Rps10 in vitro, consistent with impaired scanning arrest and gain-of-function. Additionally, G9R (same position, different substitution) and other NTT mutants (G6D, G8R, K10E) showed enhanced translation of long 5'UTR mRNAs. The exact G9D single mutant was generated but its standalone functional data were not separately reported; the G9D/R13H double mutant data and same-position G9R data are suggestive but not definitive for the isolated G9D variant. The somatic OncoKB curation classifies this variant as Likely Oncogenic with Likely Gain-of-function effect, providing additional orthogonal support.	PMID:30420357 oncokb
PS4	Not assessed	No case-control data or systematically ascertained affected vs. unaffected carrier frequencies are available for this variant. The variant has been observed in COSMIC (6 somatic occurrences) but somatic prevalence does not directly address germline PS4.
PS5	Not assessed	No evidence was identified from a reputable source (e.g., clinical diagnostic laboratory, expert panel) classifying this variant as pathogenic that is independent of the evidence already evaluated under other criteria. The ClinVar entry (VCV004539547) classifies this variant as 'Likely oncogenic' in a somatic context with a single submitter.
PM1	Met	The variant p.Gly9Asp is located in the N-terminal tail (NTT) of EIF1AX (residues ~2-15), a well-characterized functional domain critical for translation initiation fidelity. The NTT is established as a hotspot for cancer-associated somatic mutations in uveal melanoma, thyroid cancer, and ovarian cancer (PMID:30420357, PMID:30305285). Cancerhotspots.org identifies this residue as statistically significant. Multiple publications confirm that NTT mutations confer gain-of-function by impairing scanning arrest and enhancing translation of cell cycle genes. Gly9 is among the most frequently mutated residues in the NTT domain.	PMID:30420357 PMID:30305285 oncokb
PM2	Met	This variant is absent from large population databases. gnomAD v2.1: absent. gnomAD v4.1: 0 alleles out of 1,168,429 (AF = 0.0%). gnomAD-Canada v1.0: absent. The variant meets the PM2 threshold of <0.1% allele frequency in all populations.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No confirmed pathogenic missense variant at the same amino acid position (Gly9) was identified in ClinVar. The PM5 candidate harvesting pipeline could not confirm any classic same-residue comparator with a pathogenic classification. While G9R was functionally characterized alongside other NTT mutants, it lacks a ClinVar expert panel pathogenic classification.
PM6	Not assessed	No de novo data or confirmed maternity/paternity information is available. PM6 requires a confirmed de novo observation with both parental genotypes confirmed.
PP1	Not assessed	No cosegregation data with disease in multiple affected family members is available for this variant.
PP2	Not assessed	Insufficient data to determine whether EIF1AX has a low rate of benign missense variation and whether missense variants are a common disease mechanism in a germline context. While EIF1AX missense mutations are established somatic drivers, the germline missense constraint has not been systematically characterized.
PP3	Not met	In silico tools do not support a damaging effect. BayesDel score is -0.034 (negative scores predict benign). REVEL is unavailable (no coverage for chrX:20138613 in local REVEL database). SpliceAI max delta is 0.02 (no predicted splice impact). HCI prior is unavailable (gene not supported). Multiple computational lines of evidence suggest a neutral or benign effect rather than a damaging one.	bayesdel spliceai
PP4	Not assessed	No proband phenotype or clinical data is available to evaluate phenotype specificity or gene-disease fit.
PP5	Not assessed	No reputable source has independently classified this variant as pathogenic for a germline disorder. The ClinVar entry (VCV004539547) classifies it as 'Likely oncogenic' in a somatic context with criteria provided by a single submitter; this does not satisfy PP5 for germline ACMG/AMP interpretation.
BA1	Not met	The variant allele frequency in gnomAD v4.1 is 0.0% (0/1,168,429 alleles), well below the BA1 threshold of >1%. This variant is not a common polymorphism.	gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 0.0% (0/1,168,429 alleles), well below the BS1 threshold of >0.3%. The variant is too rare in the general population to support BS1.	gnomad_v4
BS2	Not assessed	No data available regarding observation of this variant in healthy adult individuals with full penetrance expected. The absence from gnomAD suggests it is not observed in healthy populations, but this alone does not satisfy the BS2 requirement for confirmed observation in a healthy adult.
BS3	Not met	Functional studies in the literature do not demonstrate a benign effect. Rather, the G9D/R13H double mutant shows reduced Rps10 binding and NTT domain mutants consistently show gain-of-function effects (enhanced scanning, increased translation of cell cycle genes) (PMID:30420357). OncoKB curation also supports Likely Gain-of-function. These findings are inconsistent with a benign functional effect.	PMID:30420357 oncokb
BS4	Not assessed	No family segregation data is available to evaluate whether the variant does not segregate with disease in affected family members.
BP1	N/A	EIF1AX has both loss-of-function and gain-of-function disease mechanisms described. Germline EIF1AX variants have been reported in uveal melanoma predisposition, and missense mutations in the NTT domain are established somatic oncogenic drivers. BP1 requires that only truncating variants cause disease, which is not the case for EIF1AX.	pvs1_gene_context
BP2	Not assessed	No data available on observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score is -0.034 (negative scores predict a benign effect). SpliceAI max delta score is 0.02, predicting no splicing impact. REVEL and HCI prior are unavailable but the available in silico tools consistently support a neutral or benign prediction.	bayesdel spliceai
BP5	Not assessed	No alternative molecular basis for disease has been identified in the available data. No proband or phenotype data are available to evaluate BP5.
BP6	Not assessed	No reputable source has classified this variant as benign or likely benign. The ClinVar entry classifies it as 'Likely oncogenic' in a somatic context, which does not inform germline BP6.
BP7	N/A	NM_001412.4:c.26G>A is a missense variant (p.Gly9Asp), not a synonymous or intronic variant. BP7 is only applicable to synonymous variants with no predicted splice impact.
BP3	N/A	Variant is a substitution, not an in-frame deletion or insertion in a repetitive region.
PM3	N/A	No data context suggesting recessive inheritance or trans configuration with a pathogenic variant. EIF1AX is X-linked and not established as a recessive disease gene.
PM4	N/A	Variant is a single-nucleotide substitution, not a protein-length-changing variant (in-frame deletion/insertion, stop-loss, or initiation codon change).

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