EIF1AXc.25G>CUncertain significance

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Variant interpretation report

EIF1AX c.25G>C, p.(Gly9Arg)

NM_001412.4:c.25G>C NP_001403.1:p.(Gly9Arg) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About EIF1AX

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 2 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 18 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PS3 (moderate): 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.
PM1 (moderate): 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.
PM2 (supporting): 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.
BP4 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 1

Pathogenic criteria applied · 3

PS3Moderate

PS3 · moderate

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.

PM1Moderate

PM1 · moderate

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.

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

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.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, BP4 supporting; combination = 2 moderate + 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

4 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV63309272, n = 4 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 16 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

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

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.

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.

Met · 4

PS3 ModerateThe 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. Details ▾Hide ▴

Evidence considered

PMID:30305285: G9R directly tested — co-IP shows increased EIF5 binding (Fig. 3B)
increased nascent protein synthesis in NthyOri cells (Fig. 3D-E).
G9R is one of three NTT mutants (G8R
G9R
G15V) tested alongside EIF1AX-c'spl
all showed increased PIC stability.

Still missing

Single study
no independent replication of G9R-specific functional effect.
Functional data derived from somatic/thyroid cancer models
germline disease mechanism for EIF1AX missense variants remains uncertain.
Observed effect is gain-of-function
while germline disease context literature suggests possible loss-of-function mechanism — mechanistic alignment requires further clarification.

Sources

PMID:30305285 ↗

PM1 ModerateThe 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. Details ▾Hide ▴

Evidence considered

Cancerhotspots.org: residue is statistically significant.
PMID:30305285: NTT domain (residues 2–15) extensively characterized as critical for PIC stability and start codon selection
mutations in this region are lethal in yeast.
COSMIC: variant observed 4 times in somatic cancers (COSV63309272).

Sources

PMID:30305285 ↗oncokb ↗

PM2 SupportingThe 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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1.
Absent from gnomAD v4.1.
Absent from gnomAD-Canada v1.0.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple 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. Details ▾Hide ▴

Evidence considered

SpliceAI: max delta 0.02 — no predicted splicing impact.
BayesDel: -0.100602 — below pathogenic threshold.

Still missing

REVEL score not available.

Sources

spliceai ↗bayesdel

Not met · 16 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴

Evidence considered

ClinVar contains no entries for NM_001412.4:c.25G>C or any other missense change at codon Gly9.

Still missing

No alternative pathogenic missense at Gly9 identified.

Sources

clinvar ↗

PS4 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. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no germline case frequency data available.

Still missing

No case-control or cohort prevalence data for this variant.

PP1 No co-segregation data is available for this variant. No family studies report segregation of NM_001412.4:c.25G>C with disease. Details ▾Hide ▴

Still missing

No family or co-segregation studies available.

PP2 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. Details ▾Hide ▴

Evidence considered

HCI prior not found for EIF1AX
no missense constraint data available.

Still missing

No HCI prior or missense constraint z-score for EIF1AX.

PP3 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. Details ▾Hide ▴

Evidence considered

BayesDel score: -0.100602 (benign range).
SpliceAI max delta: 0.02 (no splicing impact).
REVEL: not available.

Still missing

REVEL score not available for this variant.

Sources

bayesdelspliceai ↗

PP4 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. Details ▾Hide ▴

Still missing

No patient phenotype data available.

PP5 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. Details ▾Hide ▴

Evidence considered

ClinVar contains no entries for this variant.

Still missing

Variant not present in ClinVar for PP5 assessment.

Sources

clinvar ↗

BA1 The variant is absent from gnomAD; allele frequency does not exceed the 1% threshold required for BA1 (stand-alone benign). Details ▾Hide ▴

Evidence considered

Variant absent from gnomAD v2.1 and v4.1.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The variant is absent from gnomAD; allele frequency does not exceed the 0.3% threshold required for BS1. Details ▾Hide ▴

Evidence considered

Variant absent from gnomAD v2.1 and v4.1.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 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. Details ▾Hide ▴

Evidence considered

No healthy adult carriers identified in any database.

BS3 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. Details ▾Hide ▴

Evidence considered

PMID:30305285 shows G9R has increased EIF5 affinity and elevated protein synthesis
indicating functional gain rather than a benign effect.

Sources

PMID:30305285 ↗

BS4 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. Details ▾Hide ▴

Still missing

No family segregation data available.

BP1 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. Details ▾Hide ▴

Evidence considered

PMID:30305285 establishes NTT missense mutations as the primary pathogenic variant type in EIF1AX
with EIF1AX-A113splice as another recurrent class.

Sources

PMID:30305285 ↗

BP2 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. Details ▾Hide ▴

No further detail was recorded.

BP5 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. Details ▾Hide ▴

Still missing

No case data available to assess alternate molecular basis.

BP6 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. Details ▾Hide ▴

Evidence considered

ClinVar contains no entries for this variant.

Still missing

Variant not present in ClinVar for BP6 assessment.

Sources

clinvar ↗

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis 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). Details ▾Hide ▴

Evidence considered

Variant class is missense substitution
pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.

Sources

pvs1_generic_framework ↗

PS2 N/ANo de novo observation data available for this variant. No case-level data exists in ClinVar or the literature to support a de novo assessment. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo 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. Details ▾Hide ▴

Evidence considered

PM5 candidate search returned 0 same-residue candidates.

Sources

pm5_candidates

PM6 N/APM6 requires a de novo observation without confirmed maternity/paternity. No de novo data exists for this variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴

Evidence considered

Variant class is missense
not synonymous.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: EIF1AX
Transcript: NM_001412.4
Coding (HGVS c.): NM_001412.4:c.25G>C
Protein (HGVS p.): NP_001403.1:p.(Gly9Arg)
GRCh38: chrX:20138614 C>G
GRCh37: chrX:20156732 C>G
COSMIC: COSV63309272

Gene diagram

Every interpreted variant in EIF1AX, mapped onto the exon structure of NM_001412.4. Select a row to find it on the plot.

EIF1AXNM_001412.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in EIF1AX — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp

0.010

SpliceAI acceptor gainat -313 bp

0.010

SpliceAI donor lossat +0 bp

0.020

SpliceAI donor gainat -18 bp

0.010

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: -0.101

How the predictions were used

Evidence considered

SpliceAI: max delta 0.02 — no predicted splicing impact.
BayesDel: -0.100602 — below pathogenic threshold.

Still missing

REVEL score not available.

Sources

spliceai ↗bayesdel

Evidence considered

BayesDel score: -0.100602 (benign range).
SpliceAI max delta: 0.02 (no splicing impact).
REVEL: not available.

Still missing

REVEL score not available for this variant.

Sources

bayesdelspliceai ↗

Evidence considered

Variant class is missense
not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = -0.100602.

2 paper records listed. 1 cited in the classification.

Cited in the classification

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.

EIF1AX-G9R was directly tested in co-immunoprecipitation and protein synthesis assays. G9R, along with G8R and G15V, exhibited increased affinity for EIF5 compared to wild-type EIF1AX, and expression of G9R increased nascent protein synthesis in NthyOri thyroid cells, demonstrating a gain-of-function effect on translation pre-initiation complex stability.
→ PS3 → PM1 Names this variant
PMID 30305285 ↗
Source detail

EIF1AX mutants, particularly G8R, G9R and c'spl, exhibited increased affinity for EIF5

Location Results: 'EIF1AX mutants have higher affinity to components of the translation PIC and increase protein synthesis' (Fig. 3A, 3B, 3D, 3E); Discussion paragraph 1

Context Co-immunoprecipitation in HEK293T cells; L-azidohomoalanine (AHA) labeling in NthyOri thyroid cells for nascent protein synthesis

Other recorded publications

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers.

Reports genomic and transcriptomic characterization of poorly differentiated and anaplastic thyroid cancers. EIF1AX is mentioned as one of the sequenced genes in a panel of 341 cancer genes, but NM_001412.4:c.25G>C (p.Gly9Arg) was not identified in the abstract or associated study data.
Does not name this variant
PMID 26878173 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = -0.100602.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63309272, n = 4 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.