EIF1AXc.44G>TUncertain significance

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Variant interpretation report

EIF1AX c.44G>T, p.(Gly15Val)

NM_001412.4:c.44G>T NP_001403.1:p.(Gly15Val) 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) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 3 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

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

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: 2 Benign evidence criteria: 1

Pathogenic criteria applied · 2

PM1Supporting

PM1 · supporting

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.

PM2Moderate

PM2 · moderate

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.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

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.

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: PM1 supporting, PM2 moderate, BP4 supporting benign; combination = 1 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

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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 Neutral; curated oncogenicity label: Likely Neutral.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV63309316, n = 3 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.

29 criteria with recorded statuses: 3 met · 20 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 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 3

PM1 SupportingThe 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. Details ▾Hide ▴

Evidence considered

Residue at codon 15 is in a statistically significant hotspot per cancerhotspots.org.

Still missing

Hotspot designation derives from somatic cancer data
germline-specific hotspot data not available.

PM2 ModerateNM_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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
gnomAD v4.1 (0 alleles)
gnomAD-Canada v1.0 (0 alleles). Allele frequency effectively 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.01 (no splice impact). BayesDel -0.0606099 (neutral/benign range).

Still missing

REVEL not available for chrX
additional conservation metrics not assessed.

Sources

spliceai ↗bayesdel

Not met · 20 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴

Evidence considered

ClinVar search returned no matching entries or alternative nucleotide changes at this codon.

Still missing

No ClinVar entries for any variant at codon 15 of EIF1AX.

Sources

clinvar ↗

PS2 No de novo observation with confirmed parentage has been reported for this variant. Details ▾Hide ▴

Still missing

No de novo data available.

PS3 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. Details ▾Hide ▴

Evidence considered

PMID:30305285 reviewed
variant not mentioned. OncoKB Likely Neutral classification insufficient for germline PS3.

Still missing

No variant-specific functional studies available.

Sources

PMID:30305285 ↗oncokb ↗

PS4 No case-control data or statistically significant enrichment in affected individuals versus controls is available. The variant is absent from gnomAD population databases. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1
no case-control comparison possible.

Still missing

No affected cohort data available.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM5 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. Details ▾Hide ▴

Evidence considered

Zero same-residue pathogenic candidates in ClinVar
PM5 mode unknown
not eligible for classic PM5 search.

Still missing

No ClinVar entries for any missense change at codon 15.

Sources

pm5_candidatesclinvar ↗

PM6 No de novo observation, with or without confirmed parentage, has been reported for this variant. Details ▾Hide ▴

Still missing

No de novo reports.

PP1 No cosegregation data in affected family members is available. Details ▾Hide ▴

Still missing

No family segregation data.

PP2 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. Details ▾Hide ▴

Evidence considered

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

Still missing

No HCI prior or missense Z-score data.

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.01 (no splice impact). BayesDel -0.0606099 (neutral/benign range). REVEL not available.

Still missing

REVEL score unavailable for chrX.

Sources

spliceai ↗bayesdel

PP4 No patient phenotype or family history information is available to assess specificity for EIF1AX-related disease. Details ▾Hide ▴

Still missing

No proband phenotype data available.

PP5 No reputable source has reported this variant as pathogenic. This variant is absent from ClinVar entirely. Details ▾Hide ▴

Evidence considered

ClinVar has no entries for this variant.

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

Absent from all gnomAD populations
allele frequency effectively 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 The variant is absent from gnomAD population databases; allele frequency is below the 0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

Absent from all gnomAD populations
allele frequency 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 No evidence of healthy adult hemizygous or heterozygous carriers has been reported. The variant is absent from all population databases. Details ▾Hide ▴

Evidence considered

No healthy carriers identified in population databases.

Still missing

No carrier frequency data.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 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. Details ▾Hide ▴

Evidence considered

PMID:30305285 reviewed
variant not mentioned. OncoKB Likely Neutral insufficient for germline BS3.

Still missing

No variant-specific benign functional studies.

Sources

PMID:30305285 ↗oncokb ↗

BS4 No segregation data in affected family members is available to assess lack of cosegregation. Details ▾Hide ▴

Still missing

No family segregation data.

BP1 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. Details ▾Hide ▴

Evidence considered

COSMIC reports 3 somatic occurrences of this variant
hotspot analysis confirms codon 15 as a mutational hotspot
consistent with missense-driven disease mechanism.

BP2 No phase data (in cis or in trans with a pathogenic variant) is available. Details ▾Hide ▴

Still missing

No phase data.

BP5 No case has been reported in which an alternate molecular basis for disease was identified. Details ▾Hide ▴

Still missing

No cases with alternate molecular diagnosis.

BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

ClinVar has no entries for this variant.

Sources

clinvar ↗

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

PVS1 N/ANM_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). Details ▾Hide ▴

Evidence considered

Missense substitution at codon 15
variant_bucket='other'
apply_generic_pvs1_framework=false.

Sources

pvs1_generic_framework ↗

PM3 N/AEIF1AX-associated disease is not inherited in a recessive pattern; PM3 applies only to recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASubstitution variant; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants only. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASubstitution variant; BP3 applies to in-frame insertions/deletions in repetitive regions only. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_001412.4:c.44G>T is a missense (non-synonymous) variant; BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution at codon 15
not synonymous.

PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. No reputable source reports this variant as pathogenic. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: EIF1AX
Transcript: NM_001412.4
Coding (HGVS c.): NM_001412.4:c.44G>T
Protein (HGVS p.): NP_001403.1:p.(Gly15Val)
GRCh38: chrX:20138595 C>A
GRCh37: chrX:20156713 C>A
COSMIC: COSV63309316

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 -109 bp

0.000

SpliceAI acceptor gainat +21 bp

0.010

SpliceAI donor lossat +1 bp

0.010

SpliceAI donor gainat -50 bp

0.000

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: -0.061

How the predictions were used

Evidence considered

SpliceAI max delta 0.01 (no splice impact). BayesDel -0.0606099 (neutral/benign range).

Still missing

REVEL not available for chrX
additional conservation metrics not assessed.

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta 0.01 (no splice impact). BayesDel -0.0606099 (neutral/benign range). REVEL not available.

Still missing

REVEL score unavailable for chrX.

Sources

spliceai ↗bayesdel

BP7 N/ANM_001412.4:c.44G>T is a missense (non-synonymous) variant; BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution at codon 15
not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.0606099.

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

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

Functional study demonstrating EIF1AX mutations cooperate with RAS to drive thyroid tumorigenesis through ATF4 and c-MYC. NM_001412.4:c.44G>T (p.Gly15Val) was not identified in this paper.
Does not name this variant
PMID 30305285 ↗

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 0.010 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 = 0.01). BayesDel score = -0.0606099.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63309316, n = 3 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.