NM_001412.4:c.43G>T

EIF1AX · NP_001403.1:p.(Gly15Cys) · NM_001412.4

GRCh37: chrX:20156714 C>A · GRCh38: chrX:20138596 C>A

Gene: EIF1AX Transcript: NM_001412.4

Final call

VUS

PM1 moderate PM2 moderate BP4 supporting benign

Variant details

Gene

EIF1AX

Transcript

NM_001412.4

Protein

NP_001403.1:p.(Gly15Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

EIF1AX c.43G>T (p.Gly15Cys) is a missense variant located at a statistically significant mutational hotspot (cancerhotspots.org) within the N-terminal eIF1A functional domain critical for translation initiation (PM1_Moderate).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, meeting PM2 at moderate strength.

Multiple lines of in silico evidence suggest no impact on gene product: SpliceAI predicts no splicing alteration (max delta = 0.00), and BayesDel score is negative (-0.143281), consistent with a tolerated/benign prediction (BP4_Supporting).

No variant-specific functional data were identified. OncoKB notes no reviewed functional evidence for this variant, and the sole linked publication (PMID:31275557) is a pan-cancer splicing mutation resource that does not mention this variant.

ClinVar variation 4484138 has 0 submissions, no classification, and no review status, providing no clinical classification data for this variant (PS5/PP5/BP6 not met).

Overall, 2 moderate pathogenic criteria (PM1, PM2) and 1 supporting benign criterion (BP4) are met. Under the generic ACMG/AMP 2015 classification rules (PMID:25741868), this combination is insufficient to reach Likely Pathogenic (requires ≥3 moderate or 2 moderate + ≥2 supporting) and is also insufficient for Likely Benign (requires ≥1 strong benign + ≥1 supporting benign or ≥2 supporting benign). The variant is 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	Not met	This is a missense variant (NM_001412.4:c.43G>T, p.Gly15Cys) in exon 2 of EIF1AX. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable at any strength.	pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at codon 15 resulting in the same amino acid substitution (p.Gly15Cys) that is known to be pathogenic. ClinVar contains no submissions for this variant and no comparator same-amino-acid pathogenic variants were identified.	clinvar
PS2	Not met	No de novo observation data available for this variant. No family studies or trio sequencing data were identified.
PS3	Not met	No variant-specific functional data were identified. PMID 31275557 is a pan-cancer splicing mutation resource and does not mention this variant; SpliceAI predicts no splice impact (max delta = 0.00). OncoKB notes no variant-specific reviewed functional evidence. No other publications with functional characterization of p.Gly15Cys were found.	oncokb spliceai PMID:31275557
PS4	Not met	No case-control or prevalence data are available. The variant is absent from gnomAD but there is no observed case enrichment data to support statistical overrepresentation in affected individuals.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar variation 4484138 has 0 submissions, no classification, and no review status. No reputable source has reported this variant as pathogenic.	clinvar
PM1	Met	The variant is located at residue Gly15 in the N-terminal eIF1A domain of EIF1AX, a well-established functional domain critical for translation initiation. This residue lies within a statistically significant mutational hotspot (cancerhotspots.org). EIF1AX hotspot mutations in the N-terminal region are recurrent in uveal melanoma and other cancers, and no benign variation in the general population supports this being a tolerated position.	gnomad_v2 gnomad_v4
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 across all populations. Allele frequency is 0%, well below the 0.1% threshold for PM2 in the non-VCEP generic ACMG framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator pathogenic missense variants were identified. PM5 candidate harvesting returned 0 candidates at codon 15 of EIF1AX. No alternative pathogenic missense change at the same amino acid position is known.
PM6	Not met	No de novo observation data are available for this variant. No trio sequencing or parental testing data were identified in ClinVar submissions or the literature.
PP1	Not met	No cosegregation data are available. No family studies with this variant were identified.
PP2	Not met	No missense constraint data (HCI prior) are available for EIF1AX to assess whether the gene has a low rate of benign missense variation. The HCI prior lookup returned 'gene_not_supported'.
PP3	Not met	In silico predictions do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score is -0.143281, which is negative and suggests a tolerated or benign effect. REVEL score is not available for this variant. Overall, computational evidence does not support pathogenicity.	spliceai bayesdel
PP4	Not met	No patient phenotype or family history data are available in the case materials to assess whether the phenotype is highly specific for EIF1AX-related disease.
PP5	Not met	ClinVar variation 4484138 has 0 submissions, no classification, and no review status. No 3-star expert panel or other reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the 1% BA1 threshold for non-VCEP generic ACMG framework.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, below the 0.3% BS1 threshold for non-VCEP generic ACMG framework.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available on observation of this variant in healthy adults where full penetrance would be expected at an early age.
BS3	Not met	No functional studies demonstrating a neutral or benign effect of this variant were identified. The BayesDel score of -0.143281 is an in silico prediction, not a functional study, and is evaluated under BP4 rather than BS3.
BS4	Not met	No segregation data are available. No family studies were identified to assess lack of cosegregation with disease.
BP1	Not met	EIF1AX is not a gene where primarily truncating variants cause disease. The known oncogenic mechanism involves missense hotspot mutations (particularly in the N-terminal domain), and EIF1AX is recognized as an oncogene activated by gain-of-function missense alterations rather than loss-of-function truncating variants.	oncokb
BP2	Not met	No observation of this variant in trans with a known pathogenic variant is available.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.00). BayesDel score is -0.143281, which falls in the negative range predictive of a tolerated or benign effect. Although REVEL is unavailable, the concordance of available in silico tools supports a neutral prediction.	spliceai bayesdel
BP5	Not met	No case data are available identifying an alternate molecular basis for disease in a patient carrying this variant.
BP6	Not met	No reputable source reports this variant as benign. ClinVar variation 4484138 has 0 submissions and no classification.	clinvar
BP7	N/A	Missense variant (c.43G>T, p.Gly15Cys). BP7 applies only to synonymous variants without predicted splice impact. This is a non-synonymous substitution.
BP3	N/A	Substitution variant. BP3 applies to in-frame insertions/deletions in repetitive regions.
PM3	N/A	No trans observation data available in the case materials to assess PM3.
PM4	N/A	Missense substitution. PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss).

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.