About EIF1AX
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EIF1AX c.43G>T, p.(Gly15Cys)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
PM1Moderate
PM1 · moderate
The variant is located at residue Gly15 in the N-terminal eIF1A domain of EIF1AX, a well-established functional domain critical for translation initiation. This residue lies within a statistically significant mutational hotspot (cancerhotspots.org). EIF1AX hotspot mutations in the N-terminal region are recurrent in uveal melanoma and other cancers, and no benign variation in the general population supports this being a tolerated position.
PM2Moderate
PM2 · moderate
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 across all populations. Allele frequency is 0%, well below the 0.1% threshold for PM2 in the non-VCEP generic ACMG framework.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.00). BayesDel score is -0.143281, which falls in the negative range predictive of a tolerated or benign effect. Although REVEL is unavailable, the concordance of available in silico tools supports a neutral prediction.
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 moderate, PM2 moderate, BP4 supporting benign; combination = 2 moderate + 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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EIF1AX, a translation initiation factor, is most frequently altered by mutation in uveal melanomas and papillary thyroid carcinomas.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV115448712, n = 2 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
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 · 22 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
EIF1AX c.43G>T (p.Gly15Cys) is a missense variant located at a statistically significant mutational hotspot (cancerhotspots.org) within the N-terminal eIF1A functional domain critical for translation initiation (PM1_Moderate).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, meeting PM2 at moderate strength.
Multiple lines of in silico evidence suggest no impact on gene product: SpliceAI predicts no splicing alteration (max delta = 0.00), and BayesDel score is negative (-0.143281), consistent with a tolerated/benign prediction (BP4_Supporting).
No variant-specific functional data were identified. OncoKB notes no reviewed functional evidence for this variant, and the sole linked publication (PMID:31275557) is a pan-cancer splicing mutation resource that does not mention this variant.
ClinVar variation 4484138 has 0 submissions, no classification, and no review status, providing no clinical classification data for this variant (PS5/PP5/BP6 not met).
Overall, 2 moderate pathogenic criteria (PM1, PM2) and 1 supporting benign criterion (BP4) are met. Under the generic ACMG/AMP 2015 classification rules (PMID:25741868), this combination is insufficient to reach Likely Pathogenic (requires ≥3 moderate or 2 moderate + ≥2 supporting) and is also insufficient for Likely Benign (requires ≥1 strong benign + ≥1 supporting benign or ≥2 supporting benign). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM1 ModerateThe variant is located at residue Gly15 in the N-terminal eIF1A domain of EIF1AX, a well-established functional domain critical for translation initiation. This residue lies within a statistically significant mutational hotspot (cancerhotspots.org). EIF1AX hotspot mutations in the N-terminal region are recurrent in uveal melanoma and other cancers, and no benign variation in the general population supports this being a tolerated position. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org identifies residue G15 as a statistically significant hotspot
- variant absent from gnomAD
- N-terminal eIF1A domain is a critical functional domain.
Still missing
- Hotspot data is derived from somatic cancer databases
- germline-specific hotspot characterization would strengthen this criterion.
Sources
PM2 ModerateThe variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 across all populations. Allele frequency is 0%, well below the 0.1% threshold for PM2 in the non-VCEP generic ACMG framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- v4.1 (exomes)
- and gnomAD-Canada v1.0 (genomes)
- AF = 0%.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.00). BayesDel score is -0.143281, which falls in the negative range predictive of a tolerated or benign effect. Although REVEL is unavailable, the concordance of available in silico tools supports a neutral prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact)
- BayesDel = -0.143281 (negative score
- tolerated/benign prediction).
Still missing
- REVEL score unavailable for chrX.
Sources
spliceai ↗bayesdel
Not met · 22 · evaluated, threshold not reached
PVS1 This is a missense variant (NM_001412.4:c.43G>T, p.Gly15Cys) in exon 2 of EIF1AX. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable at any strength. Details ▾Hide ▴
Evidence considered
- Missense variant (p.Gly15Cys) in exon 2
- variant class 'other' not eligible for null-variant PVS1 scoring per PMC6185798.
Sources
PS1 No evidence of a different nucleotide change at codon 15 resulting in the same amino acid substitution (p.Gly15Cys) that is known to be pathogenic. ClinVar contains no submissions for this variant and no comparator same-amino-acid pathogenic variants were identified. Details ▾Hide ▴
Evidence considered
- ClinVar variation 4484138 has no submissions and no classification
- no same-amino-acid pathogenic comparator identified.
Still missing
- No same-amino-acid comparator variants found in ClinVar or literature.
Sources
PS2 No de novo observation data available for this variant. No family studies or trio sequencing data were identified. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio or family sequencing data available to assess de novo status.
PS3 No variant-specific functional data were identified. PMID 31275557 is a pan-cancer splicing mutation resource and does not mention this variant; SpliceAI predicts no splice impact (max delta = 0.00). OncoKB notes no variant-specific reviewed functional evidence. No other publications with functional characterization of p.Gly15Cys were found. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact)
- PMID 31275557 does not mention this variant
- OncoKB reports no variant-specific functional evidence.
Still missing
- No experimental functional characterization of p.Gly15Cys available in the literature.
Sources
PS4 No case-control or prevalence data are available. The variant is absent from gnomAD but there is no observed case enrichment data to support statistical overrepresentation in affected individuals. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD (no population frequency data)
- no case counts available.
Still missing
- No case-control or prevalence studies for this variant.
Sources
PM5 No same-residue comparator pathogenic missense variants were identified. PM5 candidate harvesting returned 0 candidates at codon 15 of EIF1AX. No alternative pathogenic missense change at the same amino acid position is known. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 candidates
- no known pathogenic missense change at codon 15.
Still missing
- No comparator pathogenic missense variants at codon 15.
PM6 No de novo observation data are available for this variant. No trio sequencing or parental testing data were identified in ClinVar submissions or the literature. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No de novo testing data.
PP1 No cosegregation data are available. No family studies with this variant were identified. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies or cosegregation analysis.
PP2 No missense constraint data (HCI prior) are available for EIF1AX to assess whether the gene has a low rate of benign missense variation. The HCI prior lookup returned 'gene_not_supported'. Details ▾Hide ▴
Evidence considered
- HCI prior not available for EIF1AX (gene_not_supported).
Still missing
- No missense constraint metric available for EIF1AX.
PP3 In silico predictions do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score is -0.143281, which is negative and suggests a tolerated or benign effect. REVEL score is not available for this variant. Overall, computational evidence does not support pathogenicity. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- BayesDel = -0.143281 (tolerated/benign prediction)
- REVEL not available.
Still missing
- REVEL score unavailable for chrX variant.
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or family history data are available in the case materials to assess whether the phenotype is highly specific for EIF1AX-related disease. Details ▾Hide ▴
Evidence considered
- No patient phenotype data provided.
Still missing
- No clinical phenotype information available for the proband.
PP5 ClinVar variation 4484138 has 0 submissions, no classification, and no review status. No 3-star expert panel or other reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar variation 4484138: 0 submissions
- no expert panel classification
- no pathogenic assertion from any submitter.
Still missing
- No ClinVar classification from any submitter or expert panel.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the 1% BA1 threshold for non-VCEP generic ACMG framework. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- AF = 0%.
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, below the 0.3% BS1 threshold for non-VCEP generic ACMG framework. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- AF = 0%.
Sources
BS2 No data are available on observation of this variant in healthy adults where full penetrance would be expected at an early age. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No data on variant observation in healthy adults.
BS3 No functional studies demonstrating a neutral or benign effect of this variant were identified. The BayesDel score of -0.143281 is an in silico prediction, not a functional study, and is evaluated under BP4 rather than BS3. Details ▾Hide ▴
Evidence considered
- No functional studies available.
Still missing
- No experimental functional characterization of p.Gly15Cys.
BS4 No segregation data are available. No family studies were identified to assess lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation data.
BP1 EIF1AX is not a gene where primarily truncating variants cause disease. The known oncogenic mechanism involves missense hotspot mutations (particularly in the N-terminal domain), and EIF1AX is recognized as an oncogene activated by gain-of-function missense alterations rather than loss-of-function truncating variants. Details ▾Hide ▴
Evidence considered
- EIF1AX is an oncogene where missense
- not truncating
- variants are the primary disease mechanism
- OncoKB classifies variant as 'Likely Oncogenic'.
Sources
BP2 No observation of this variant in trans with a known pathogenic variant is available. Details ▾Hide ▴
Evidence considered
- No trans observation data available.
Still missing
- No trans phasing data.
BP5 No case data are available identifying an alternate molecular basis for disease in a patient carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No data on alternate molecular diagnoses.
BP6 No reputable source reports this variant as benign. ClinVar variation 4484138 has 0 submissions and no classification. Details ▾Hide ▴
Evidence considered
- ClinVar variation 4484138: 0 submissions
- no classification.
Still missing
- No benign classification from any source.
Sources
PS5 ClinVar variation 4484138 has 0 submissions, no classification, and no review status. No reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar variation 4484138: 0 submissions
- no classification
- no review status.
Still missing
- No ClinVar classification from any submitter.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ANo trans observation data available in the case materials to assess PM3. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AMissense substitution. PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss). Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASubstitution variant. BP3 applies to in-frame insertions/deletions in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AMissense variant (c.43G>T, p.Gly15Cys). BP7 applies only to synonymous variants without predicted splice impact. This is a non-synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- EIF1AX
- Transcript
- NM_001412.4
- Coding (HGVS c.)
- NM_001412.4:c.43G>T
- Protein (HGVS p.)
- NP_001403.1:p.(Gly15Cys)
- GRCh38
- chrX:20138596 C>A
- GRCh37
- chrX:20156714 C>A
- ClinVar
- 4484138
- COSMIC
- COSV115448712
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
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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
Other predictors
- REVEL
- Not available
- BayesDel
- -0.143
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.00). BayesDel score is -0.143281, which falls in the negative range predictive of a tolerated or benign effect. Although REVEL is unavailable, the concordance of available in silico tools supports a neutral prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact)
- BayesDel = -0.143281 (negative score
- tolerated/benign prediction).
Still missing
- REVEL score unavailable for chrX.
Sources
spliceai ↗bayesdel
PP3 In silico predictions do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score is -0.143281, which is negative and suggests a tolerated or benign effect. REVEL score is not available for this variant. Overall, computational evidence does not support pathogenicity. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- BayesDel = -0.143281 (tolerated/benign prediction)
- REVEL not available.
Still missing
- REVEL score unavailable for chrX variant.
Sources
spliceai ↗bayesdel
BP7 N/AMissense variant (c.43G>T, p.Gly15Cys). BP7 applies only to synonymous variants without predicted splice impact. This is a non-synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.143281.
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
-
PMID 31275557 ↗Pan-cancer repository of validated natural and cryptic mRNA splicing mutations.Shirley BC et al. · 2018Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. The dataset catalogs splicing-altering variants across TCGA and ICGC tumor types. NM_001412.4:c.43G>T was not identified in this paper. This is consistent with SpliceAI predicting no splice impact for this variant (max delta = 0.00).Does not name this variant
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 0.000
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/4484138/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-20156714-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-20138596-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-20138596-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001412.4%3Ac.43G%…
- OncoKB ↗www.oncokb.org/gene/EIF1AX/G15C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=144404603
- Cancer hotspots ↗www.cancerhotspots.org/
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 has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4484138)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.143281.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EIF1AX, a translation initiation factor, is most frequently altered by mutation in uveal melanomas and papillary thyroid carcinomas.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV115448712, n = 2 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.