Variant classification summary

NM_001412.4:c.25G>C

EIF1AX · NP_001403.1:p.(Gly9Arg) · NM_001412.4

GRCh37: chrX:20156732 C>G · GRCh38: chrX:20138614 C>G

Gene: EIF1AX Transcript: NM_001412.4

Final call

VUS

PS3 moderate PM1 moderate PM2 supporting BP4 supporting

Variant details

Gene

EIF1AX

Transcript

NM_001412.4

Protein

NP_001403.1:p.(Gly9Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), supporting PM2 at supporting strength.

4

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.

5

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.

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 missense variant (p.Gly9Arg) does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No known pathogenic variant with a different amino acid substitution at the same codon (Gly9) is present in ClinVar or the published literature. The variant is absent from ClinVar entirely.	clinvar
PS2	N/A	No de novo observation data available for this variant. No case-level data exists in ClinVar or the literature to support a de novo assessment.
PS3	Met	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
PS4	Not met	No case-control data or affected vs. control prevalence comparison is available for this variant. The variant is absent from ClinVar and is not reported in any germline cohort.
PS5	N/A	PS5 is a de novo criterion requiring a de novo observation (with unconfirmed maternity/paternity). No de novo data exists for this variant in any source.
PM1	Met	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.	PMID:30305285 oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic comparator variants at the same amino acid position (Gly9) with a different missense substitution were identified in ClinVar or the literature. The pm5_candidates search confirms no eligible comparators.	pm5_candidates
PM6	N/A	PM6 requires a de novo observation without confirmed maternity/paternity. No de novo data exists for this variant.
PP1	Not met	No co-segregation data is available for this variant. No family studies report segregation of NM_001412.4:c.25G>C with disease.
PP2	Not met	HCI prior score is not available for EIF1AX. Insufficient evidence to determine whether EIF1AX has a low rate of benign missense variation and whether missense variants are a common disease mechanism as required for PP2.
PP3	Not met	In silico predictors do not support a deleterious effect. BayesDel score is -0.100602 (below typical pathogenic threshold). SpliceAI predicts no splicing impact (max delta 0.02). REVEL score is not available. Multiple lines of computational evidence are required for PP3, and the available scores do not support pathogenicity.	bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data is available for this variant. PP4 requires the patient's phenotype or family history to be highly specific for the gene-associated disease, which cannot be assessed without clinical data.
PP5	Not met	The variant is absent from ClinVar. PP5 requires classification as pathogenic by a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory), which is not available.	clinvar
BA1	Not met	The variant is absent from gnomAD; allele frequency does not exceed the 1% threshold required for BA1 (stand-alone benign).	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD; allele frequency does not exceed the 0.3% threshold required for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in healthy adults has been reported. The variant is absent from all population databases. BS2 requires observation in healthy individuals where full penetrance is expected at an early age.
BS3	Not met	No well-established functional studies demonstrate a neutral or benign effect. The available functional data (PMID:30305285) shows that G9R exhibits a gain-of-function effect — increased EIF5 binding and increased protein synthesis — which is not consistent with a benign interpretation.	PMID:30305285
BS4	Not met	No segregation data is available to assess lack of co-segregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members.
BP1	Not met	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. BP1 applies only when truncating variants are the established disease mechanism.	PMID:30305285
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in a gene associated with recessive disease. EIF1AX is X-linked; BP2 is not applicable to an X-linked gene in this context.
BP4	Met	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 bayesdel
BP5	Not met	No evidence that this variant is observed in a case with an alternate molecular basis for disease. BP5 requires identification of an alternative causative variant in a case harboring this variant.
BP6	Not met	The variant is absent from ClinVar. BP6 requires classification as benign by a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory), which is not available.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_001412.4:c.25G>C is a missense variant (p.Gly9Arg) and does not meet the criteria for BP7.

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