NM_001412.4:c.44G>T

EIF1AX · NP_001403.1:p.(Gly15Val) · NM_001412.4

GRCh37: chrX:20156713 C>A · GRCh38: chrX:20138595 C>A

Gene: EIF1AX Transcript: NM_001412.4

Final call

VUS

PM1 supporting PM2 moderate BP4 supporting benign

Variant details

Gene

EIF1AX

Transcript

NM_001412.4

Protein

NP_001403.1:p.(Gly15Val)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001412.4:c.44G>T (p.Gly15Val) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).

The p.Gly15Val residue maps to a statistically significant mutational hotspot (PM1_supporting).

Multiple in silico predictors suggest no damaging effect: SpliceAI delta 0.01 and BayesDel -0.06 are both consistent with a neutral effect (BP4_supporting_benign).

One moderate and one supporting pathogenic criterion are countered by one supporting benign criterion. The overall evidence does not meet the threshold for likely pathogenic (requires ≥2 moderate, or 1 moderate + ≥2 supporting) or likely benign (requires ≥2 supporting benign). The variant is classified as a Variant of Uncertain Significance per generic ACMG/AMP 2015 combination rules.

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.44G>T is a missense variant (p.Gly15Val) and does not fall into the null variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at the same codon producing the same G15V missense alteration that has been classified as pathogenic. This variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No de novo observation with confirmed parentage has been reported for this variant.
PS3	Not met	PMID:30305285 is a functional study of EIF1AX in thyroid cancer but does not mention NM_001412.4:c.44G>T (p.Gly15Val) specifically. OncoKB annotates G15V as Likely Neutral but this single somatic oncology annotation does not constitute well-established functional evidence in the germline context.	PMID:30305285 oncokb
PS4	Not met	No case-control data or statistically significant enrichment in affected individuals versus controls is available. The variant is absent from gnomAD population databases.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. No reputable source reports this variant as pathogenic.
PM1	Met	The p.Gly15Val residue maps to a statistically significant mutational hotspot as identified by cancerhotspots.org, and is located in the N-terminal region of EIF1AX where recurrent somatic mutations cluster.
PM2	Met	NM_001412.4:c.44G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. EIF1AX is located on the X chromosome, further supporting that absence in population databases is significant.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Gly15) has been identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants.	pm5_candidates clinvar
PM6	Not met	No de novo observation, with or without confirmed parentage, has been reported for this variant.
PP1	Not met	No cosegregation data in affected family members is available.
PP2	Not met	No missense constraint data (HCI prior) is available for EIF1AX. The gene is located on the X chromosome and a low rate of benign missense variation has not been established for germline disease context.
PP3	Not met	Multiple in silico tools predict a neutral effect. SpliceAI predicts no splicing impact (max delta score 0.01). BayesDel score is -0.06, falling in the neutral/benign range. REVEL is not available. The computational evidence does not support a deleterious effect.	spliceai bayesdel
PP4	Not met	No patient phenotype or family history information is available to assess specificity for EIF1AX-related disease.
PP5	Not met	No reputable source has reported this variant as pathogenic. This variant is absent from ClinVar entirely.	clinvar
BA1	Not met	NM_001412.4:c.44G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD population databases; allele frequency is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of healthy adult hemizygous or heterozygous carriers has been reported. The variant is absent from all population databases.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no damaging effect for NM_001412.4:c.44G>T specifically. PMID:30305285 was reviewed and does not mention this variant. OncoKB annotation of Likely Neutral is a somatic oncology classification that does not meet the threshold for germline BS3.	PMID:30305285 oncokb
BS4	Not met	No segregation data in affected family members is available to assess lack of cosegregation.
BP1	Not met	While loss-of-function is supported as a disease mechanism for EIF1AX, the known pathogenic variants in EIF1AX-associated uveal melanoma and thyroid cancer are predominantly missense hotspot mutations. The gene does not have a disease mechanism limited primarily to truncating variants.
BP2	Not met	No phase data (in cis or in trans with a pathogenic variant) is available.
BP4	Met	Multiple lines of computational evidence suggest no damaging effect. SpliceAI predicts no splicing impact (max delta score 0.01). BayesDel score of -0.06 falls in the neutral/benign range. Two independent in silico predictors agree on a neutral effect.	spliceai bayesdel
BP5	Not met	No case has been reported in which an alternate molecular basis for disease was identified.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_001412.4:c.44G>T is a missense (non-synonymous) variant; BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Substitution variant; BP3 applies to in-frame insertions/deletions in repetitive regions only.
PM3	N/A	EIF1AX-associated disease is not inherited in a recessive pattern; PM3 applies only to recessive disorders.
PM4	N/A	Substitution variant; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants only.

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.