NM_001412.4:c.17G>T

EIF1AX · NP_001403.1:p.(Gly6Val) · NM_001412.4

GRCh37: chrX:20156740 C>A · GRCh38: chrX:20138622 C>A

Gene: EIF1AX Transcript: NM_001412.4

Final call

VUS

PM1 moderate PM2 supporting BP4 supporting benign

Variant details

Gene

EIF1AX

Transcript

NM_001412.4

Protein

NP_001403.1:p.(Gly6Val)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001412.4:c.17G>T (p.Gly6Val) is a missense variant in the N-terminal tail (NTT) of EIF1AX, a critical functional domain involved in ribosomal scanning, AUG selection, and ribosomal protein binding.

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, indicating it is a rare variant not observed in large control populations.

Residue Gly6 lies within a statistically significant mutational hotspot (cancerhotspots.org) and within the NTT functional domain, where recurrent missense mutations are documented in uveal melanoma. Functional studies of the G6D substitution at the same residue demonstrate altered translational regulation and reduced Rps10 binding.

Multiple in silico tools predict no significant deleterious impact: BayesDel score is -0.263 (benign-leaning) and SpliceAI predicts no splicing alteration (max delta score = 0.00).

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (ClinVar ID: 1708311). It has been observed in somatic cancers (COSMIC; n=2) but no germline clinical or functional evidence specific to this variant is available.

No functional studies have directly tested the G6V substitution. Available functional data for other NTT mutants (G6D, G8R/G9R, K10E, R13H, G15D) demonstrate a gain-of-function mechanism with altered translational control, but these studies do not constitute variant-specific evidence for G6V.

No de novo, segregation, or case-control data are available for this variant.

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	PVS1 is not applicable. NM_001412.4:c.17G>T is a missense variant (p.Gly6Val) and does not meet the null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required by the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at codon 6 that would result in the same amino acid substitution (Gly6Val) has been identified in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence of NM_001412.4:c.17G>T has been reported in the literature or in ClinVar submissions. No parental testing data available.	clinvar
PS3	Not met	No functional studies directly tested NM_001412.4:c.17G>T (p.Gly6Val). While PMID:30420357 and PMID:28594900 tested a different substitution at the same residue (G6D) and demonstrated altered translational regulation and reduced Rps10 binding for EIF1AX NTT mutants, the exact variant has not been experimentally characterized. Domain-level inference from a different substitution at the same residue does not satisfy PS3 requirements for variant-specific functional evidence.	PMID:30420357 PMID:28594900
PS4	Not met	No case-control or statistical enrichment data are available for this variant. The single ClinVar submission is a VUS from one clinical laboratory; no cohort-level association data exist.	clinvar
PS5	Not met	This variant has not been asserted as pathogenic by a reputable source (ClinGen expert panel, clinical practice guideline, or validated functional study). ClinVar classification is Uncertain significance, single submitter.	clinvar
PM1	Met	Residue Gly6 is located within the N-terminal tail (NTT) of EIF1AX (amino acids 1–15), a well-characterized functional domain critical for translational regulation, ribosomal scanning, AUG selection, and Rps3/Rps10 binding (PMID:30420357, PMID:28594900). This position lies within a statistically significant mutational hotspot identified by cancerhotspots.org, and the NTT is recurrently mutated in uveal melanoma. Missense alterations in this domain have been shown to alter EIF1AX function.	PMID:30420357 PMID:28594900
PM2	Met	This variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting the PM2 threshold of <0.1% population frequency for a rare variant absent from controls.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same codon (Gly6) has been identified in ClinVar or the literature with an established pathogenic classification. G6D has been studied experimentally (PMID:30420357, PMID:28594900) but is not classified as pathogenic in ClinVar and does not satisfy PM5 requirements for a known pathogenic comparator at the same residue.	clinvar PMID:30420357 PMID:28594900
PM6	Not met	No de novo observation of this variant (with or without confirmed paternity/maternity) has been reported in the literature or ClinVar.	clinvar
PP1	Not met	No segregation data are available for this variant. No family studies or cosegregation analyses have been reported.
PP2	Not assessed	Insufficient data to assess PP2. EIF1AX is an X-linked gene with recurrent missense mutations in the NTT domain. However, no gene-specific missense constraint metrics (z-score, HCI prior) are available for this gene. PP2 requires a low rate of benign missense variation and evidence that missense variants are a common disease mechanism — while the literature supports a gain-of-function missense mechanism, population-level constraint data are lacking.
PP3	Not met	In silico tools do not support a deleterious effect. BayesDel score is -0.263 (benign-leaning), SpliceAI predicts no splicing impact (max delta score = 0.00), and REVEL is unavailable. Multiple lines of computational evidence do not agree on a deleterious prediction.	bayesdel spliceai
PP4	Not met	No patient-specific phenotype or clinical data are available for this case. PP4 requires the variant to be found in a patient whose phenotype or family history is highly specific for the disease.
PP5	Not met	ClinVar classification is Uncertain significance from a single submitter. PP5 requires a pathogenic assertion from a reputable source; VUS classification with criteria provided, single submitter does not meet this threshold.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency >0.3% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adults. EIF1AX is X-linked; hemizygous presence in healthy adult males or homozygous presence in healthy females would support BS2, but no such observations exist.	gnomad_v2 gnomad_v4
BS3	Not met	Functional studies of EIF1AX NTT mutants (including G6D at the same residue, PMID:30420357, PMID:28594900) demonstrate altered translational regulation, reduced Rps10 binding, and enhanced scanning of long 5'UTR mRNAs — all indicative of a functional effect rather than no damaging effect. BS3 requires well-established studies showing no damaging effect on protein function or splicing; the available evidence shows the opposite.	PMID:30420357 PMID:28594900
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available. No family studies have been reported for this variant.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. EIF1AX-associated disease (uveal melanoma) is driven by gain-of-function missense mutations in the N-terminal tail, not by truncating loss-of-function variants. Nonsense and frameshift mutations have not been observed in UM tumors; all recurrent EIF1AX mutations are non-synonymous substitutions in the NTT (PMID:28594900).	PMID:28594900
BP2	Not met	No observation of this variant in trans with a pathogenic variant in a gene for a fully penetrant dominant/recessive disorder. EIF1AX is X-linked; BP2 is generally not applicable in this context without specific data.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign effect (score -0.263, below the deleterious threshold) and SpliceAI predicts no splicing alteration (max delta score = 0.00). REVEL is not available for this variant.	bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternative molecular basis for disease. No such data are available in the case materials or literature.
BP6	Not met	No reputable source has classified this variant as benign or likely benign. ClinVar classification is Uncertain significance from a single submitter.	clinvar
BP7	N/A	BP7 applies only to synonymous variants with no predicted splicing impact. NM_001412.4:c.17G>T is a missense variant (p.Gly6Val).
BP3	N/A	BP3 applies only to in-frame deletions/insertions in repetitive regions. This variant is a single nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. EIF1AX is X-linked and associated disease is not recessive.
PM4	N/A	PM4 applies only to non-repeat in-frame deletions/insertions or stop-loss variants causing protein length change. This variant is a single nucleotide substitution producing a missense change.

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