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EIF1AX
Final classification
VUS
EIF1AX c.44G>T · p.Gly15Val
EIF1AX

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

Gene
EIF1AX
Transcript
NM_001412.4
HGVS · transcript:coding
NM_001412.4:c.44G>T
Consequence
N/A
GRCh38
chrX:20138595 C>A
GRCh37
chrX:20156713 C>A
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2 BP4 VUS
EIF1AX c.44G>T

NM_001412.4:c.44G>T (p.Gly15Val) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).1 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).2 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.3

PM1 + PM2 + BP4 VUS
2 spliceai ↗bayesdel
3 generic_acmg_combination_rules
Gene diagram · NM_001412.4 · variants mapped to exon structure
EIF1AX NM_001412.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.0606099.
      Functional / OncoKB screenshot
      Functional Likely Neutral
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Hotspot
      COSMIC
      This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63309316, n = 3 times).
      Hotspots
      This variant lies in a statistically significant hotspot.
      Sources & reference links
      8Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 1 PMID not cited in assessment
      30305285 ↗ EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC. ONCOKB