NM_001412.4:c.5C>T

EIF1AX · NP_001403.1:p.(Pro2Leu) · NM_001412.4

GRCh37: chrX:20159754 G>A · GRCh38: chrX:20141636 G>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.(Pro2Leu)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The variant is located at codon 2 (p.Pro2Leu), a statistically significant mutational hotspot residue in EIF1AX, a well-established driver gene in uveal melanoma (PM1_moderate).

The variant is completely absent from gnomAD v4.1 (0/1,155,341 alleles), gnomAD v2.1, and gnomAD Canada, meeting the PM2 criterion for absence from population databases (PM2_moderate).

BayesDel predicts a benign score of -0.368928, and SpliceAI predicts no splice impact (max delta 0.00), providing multiple lines of computational evidence against a damaging effect (BP4_supporting).

No functional studies, de novo reports, segregation data, or ClinVar classifications exist for this variant. PS3, PS2, PP1, PP5, and BS3 are not met. PVS1, PM5, and BP7 are not applicable to this missense 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	This is a missense substitution (c.5C>T, p.Pro2Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No prior pathogenic variant with the same amino acid change (P2L) has been established in ClinVar or the literature. Without a previously classified pathogenic comparator at this residue with the same change, PS1 cannot be applied.	clinvar
PS2	Not met	No de novo occurrence data with confirmed paternity and maternity is available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies directly testing this variant were identified. OncoKB annotates the variant as Likely Oncogenic in a somatic context but provides no curated PMIDs or experimental data for independent review. COSMIC reports 7 somatic observations without functional characterization. The cancerhotspots.org residue-level significance constitutes domain-level (PM1) evidence, not variant-specific functional evidence for PS3.	oncokb
PS4	Not met	No case-control data comparing variant prevalence in affected versus unaffected individuals is available.
PS5	Not met	This variant has not been reported as pathogenic by a reputable source where the underlying evidence is unavailable for independent evaluation. The variant is absent from ClinVar and no other germline classification source has assessed it.	clinvar
PM1	Met	The variant is located at codon 2 (p.Pro2Leu) in EIF1AX, a residue within a statistically significant mutational hotspot identified by cancerhotspots.org. EIF1AX is a well-established driver gene in uveal melanoma, and the N-terminal region encompassing codon 2 is critical for translation initiation function. The variant is completely absent from gnomAD, consistent with a functionally constrained residue.	gnomad_v4 oncokb
PM2	Met	This variant is completely absent from population databases. gnomAD v4.1 reports 0 alleles in 1,155,341 alleles (AF=0.00%), gnomAD v2.1 reports absence, and gnomAD Canada reports absence. The allele frequency of 0% is well below the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No comparator missense variant at codon 2 with a different amino acid change has been established as pathogenic. PM5 requires a different missense change at the same residue that is already classified as pathogenic.	pm5_candidates
PM6	Not met	No de novo occurrence data (without confirmed paternity and maternity) is available for this variant.
PP1	Not met	No cosegregation data in affected family members is available for this variant.
PP2	Not met	Insufficient constraint data to determine whether EIF1AX has a low rate of benign missense variation. No gnomAD missense Z-score or observed/expected ratio is available. HCI prior is not supported for this gene.
PP3	Not met	Computational evidence does not support a deleterious effect. BayesDel predicts a benign score of -0.368928 (deleterious threshold >0.27). REVEL is not available. SpliceAI predicts no splice impact (max delta 0.00), which is neutral rather than supportive of pathogenicity.	bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available to assess specificity for a disease with a single genetic etiology.
PP5	Not met	This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. No expert panel or clinical laboratory has classified this variant.	clinvar
BA1	Not met	The variant allele frequency is 0.00% in gnomAD v4.1 (0/1,155,341 alleles), far below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	The variant allele frequency is 0.00% in gnomAD v4.1, far below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not met	No data on observation in healthy adult individuals for a fully penetrant disorder is available.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant are available.
BS4	Not met	No segregation data in affected family members is available to assess lack of segregation.
BP1	Not met	EIF1AX is an oncogene in which missense variants are the primary established disease mechanism, not a gene where primarily truncating variants cause disease. Germline literature review (PMID:39344744) explicitly reports that EIF1AX lacked pathogenic germline variants in a uveal melanoma cohort, and the known oncogenic mechanism is gain-of-function via missense mutations in the N-terminal domain.	pvs1_gene_context
BP2	Not met	No data on observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, is available.
BP4	Met	Multiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.368928 (well below the deleterious threshold of 0.27), integrating conservation, evolutionary, and biochemical features. SpliceAI predicts no splice impact (max delta score 0.00).	bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not met	This variant is absent from ClinVar and has not been reported as benign by any reputable source.	clinvar
BP7	N/A	This is a missense variant (c.5C>T, p.Pro2Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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