About EIF1AX
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EIF1AX c.17G>T, p.(Gly6Val)
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
Residue Gly6 is located within the N-terminal tail (NTT) of EIF1AX (amino acids 1–15), a well-characterized functional domain critical for translational regulation, ribosomal scanning, AUG selection, and Rps3/Rps10 binding (PMID:30420357, PMID:28594900). This position lies within a statistically significant mutational hotspot identified by cancerhotspots.org, and the NTT is recurrently mutated in uveal melanoma. Missense alterations in this domain have been shown to alter EIF1AX function.
PM2Supporting
PM2 · supporting
This variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting the PM2 threshold of <0.1% population frequency for a rare variant absent from controls.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign effect (score -0.263, below the deleterious threshold) and SpliceAI predicts no splicing alteration (max delta score = 0.00). REVEL is not available for this variant.
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 supporting, 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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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; COSV105919481, 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 · 20 not met · 1 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001412.4:c.17G>T (p.Gly6Val) is a missense variant in the N-terminal tail (NTT) of EIF1AX, a critical functional domain involved in ribosomal scanning, AUG selection, and ribosomal protein binding.
This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, indicating it is a rare variant not observed in large control populations.
Residue Gly6 lies within a statistically significant mutational hotspot (cancerhotspots.org) and within the NTT functional domain, where recurrent missense mutations are documented in uveal melanoma. Functional studies of the G6D substitution at the same residue demonstrate altered translational regulation and reduced Rps10 binding.
Multiple in silico tools predict no significant deleterious impact: BayesDel score is -0.263 (benign-leaning) and SpliceAI predicts no splicing alteration (max delta score = 0.00).
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (ClinVar ID: 1708311). It has been observed in somatic cancers (COSMIC; n=2) but no germline clinical or functional evidence specific to this variant is available.
No functional studies have directly tested the G6V substitution. Available functional data for other NTT mutants (G6D, G8R/G9R, K10E, R13H, G15D) demonstrate a gain-of-function mechanism with altered translational control, but these studies do not constitute variant-specific evidence for G6V.
No de novo, segregation, or case-control data are available for this variant.
No criteria match.
Met · 3
PM1 ModerateResidue Gly6 is located within the N-terminal tail (NTT) of EIF1AX (amino acids 1–15), a well-characterized functional domain critical for translational regulation, ribosomal scanning, AUG selection, and Rps3/Rps10 binding (PMID:30420357, PMID:28594900). This position lies within a statistically significant mutational hotspot identified by cancerhotspots.org, and the NTT is recurrently mutated in uveal melanoma. Missense alterations in this domain have been shown to alter EIF1AX function. Details ▾Hide ▴
Evidence considered
- NTT (aa 1–15) is a critical functional domain for ribosomal protein binding and translation initiation (PMID:30420357
- PMID:28594900). cancerhotspots.org identifies this residue as a statistically significant mutational hotspot. Recurrent NTT mutations are documented across UM cohorts.
Sources
PM2 SupportingThis variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting the PM2 threshold of <0.1% population frequency for a rare variant absent from controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada v1.0 (0 alleles).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign effect (score -0.263, below the deleterious threshold) and SpliceAI predicts no splicing alteration (max delta score = 0.00). REVEL is not available for this variant. Details ▾Hide ▴
Evidence considered
- BayesDel score: -0.263 (benign range). SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
bayesdelspliceai ↗
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 6 that would result in the same amino acid substitution (Gly6Val) has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar variation 1708311 is the only record for this variant
- no alternative nucleotide change at codon 6 with same protein consequence identified.
Sources
PS2 No de novo occurrence of NM_001412.4:c.17G>T has been reported in the literature or in ClinVar submissions. No parental testing data available. Details ▾Hide ▴
Evidence considered
- ClinVar submission SCV002577812 is somatic origin
- no de novo germline report found.
Sources
PS3 No functional studies directly tested NM_001412.4:c.17G>T (p.Gly6Val). While PMID:30420357 and PMID:28594900 tested a different substitution at the same residue (G6D) and demonstrated altered translational regulation and reduced Rps10 binding for EIF1AX NTT mutants, the exact variant has not been experimentally characterized. Domain-level inference from a different substitution at the same residue does not satisfy PS3 requirements for variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- G6D (different substitution at same Gly6 residue) showed reduced Rps10 binding (PMID:30420357) and altered polysome profiles with impaired ribosomal protein translational regulation (PMID:28594900). G6V was not directly tested.
Still missing
- No functional study has directly tested the G6V substitution.
Sources
PS4 No case-control or statistical enrichment data are available for this variant. The single ClinVar submission is a VUS from one clinical laboratory; no cohort-level association data exist. Details ▾Hide ▴
Evidence considered
- ClinVar variation 1708311: single submitter
- classification Uncertain significance
- no case-control data.
Still missing
- No case-control or cohort enrichment studies for this variant.
Sources
PM5 No pathogenic missense variant at the same codon (Gly6) has been identified in ClinVar or the literature with an established pathogenic classification. G6D has been studied experimentally (PMID:30420357, PMID:28594900) but is not classified as pathogenic in ClinVar and does not satisfy PM5 requirements for a known pathogenic comparator at the same residue. Details ▾Hide ▴
Evidence considered
- No ClinVar pathogenic/likely pathogenic missense variant at codon 6. G6D characterized in experimental studies but not classified as pathogenic in ClinVar. pm5_candidates.json returned zero eligible comparators.
Sources
PM6 No de novo observation of this variant (with or without confirmed paternity/maternity) has been reported in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar submission SCV002577812 has somatic origin
- no de novo germline report. No de novo reports found in literature.
Sources
PP1 No segregation data are available for this variant. No family studies or cosegregation analyses have been reported. Details ▾Hide ▴
Evidence considered
- No segregation or family studies identified in literature or ClinVar.
Still missing
- No segregation data available.
PP3 In silico tools do not support a deleterious effect. BayesDel score is -0.263 (benign-leaning), SpliceAI predicts no splicing impact (max delta score = 0.00), and REVEL is unavailable. Multiple lines of computational evidence do not agree on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- BayesDel score: -0.263 (benign range). SpliceAI max delta: 0.00 (no splice impact). REVEL: not available.
Sources
bayesdelspliceai ↗
PP4 No patient-specific phenotype or clinical data are available for this case. PP4 requires the variant to be found in a patient whose phenotype or family history is highly specific for the disease. Details ▾Hide ▴
Evidence considered
- No phenotype data
- clinical history
- or family history provided in case materials.
Still missing
- Phenotype data not available for this case.
PP5 ClinVar classification is Uncertain significance from a single submitter. PP5 requires a pathogenic assertion from a reputable source; VUS classification with criteria provided, single submitter does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar variation 1708311: classification Uncertain significance
- review status 'criteria provided
- single submitter'
- submitter: Centre of Medical Genetics
- University Hospital Muenster.
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- allele frequency is 0%.
Sources
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency >0.3% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- allele frequency is 0%.
Sources
BS2 No data are available regarding observation of this variant in healthy adults. EIF1AX is X-linked; hemizygous presence in healthy adult males or homozygous presence in healthy females would support BS2, but no such observations exist. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no observations in healthy controls.
Still missing
- No healthy control screening data specific to this variant.
Sources
BS3 Functional studies of EIF1AX NTT mutants (including G6D at the same residue, PMID:30420357, PMID:28594900) demonstrate altered translational regulation, reduced Rps10 binding, and enhanced scanning of long 5'UTR mRNAs — all indicative of a functional effect rather than no damaging effect. BS3 requires well-established studies showing no damaging effect on protein function or splicing; the available evidence shows the opposite. Details ▾Hide ▴
Evidence considered
- G6D NTT mutant shows reduced Rps10 binding (PMID:30420357) and altered polysome profiles with impaired ribosomal protein translational regulation (PMID:28594900). NTT mutants are gain-of-function
- not neutral.
Sources
BS4 No segregation data demonstrating lack of cosegregation with disease are available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or cosegregation studies identified.
Still missing
- No family segregation data available.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. EIF1AX-associated disease (uveal melanoma) is driven by gain-of-function missense mutations in the N-terminal tail, not by truncating loss-of-function variants. Nonsense and frameshift mutations have not been observed in UM tumors; all recurrent EIF1AX mutations are non-synonymous substitutions in the NTT (PMID:28594900). Details ▾Hide ▴
Evidence considered
- PMID:28594900: 'All EIF1AX mutations in our UM cohort were non-synonymous and localized within the unstructured N-terminal tail (NTT)...no inactivating mutations such as nonsense or frameshift mutations were observed. Together
- these observations raise the possibility of a gain-of-function mutational event.'
Sources
BP2 No observation of this variant in trans with a pathogenic variant in a gene for a fully penetrant dominant/recessive disorder. EIF1AX is X-linked; BP2 is generally not applicable in this context without specific data. Details ▾Hide ▴
Evidence considered
- No trans-configuration data available. X-linked gene
- BP2 application limited.
BP5 No observation of this variant in a case with an alternative molecular basis for disease. No such data are available in the case materials or literature. Details ▾Hide ▴
Evidence considered
- No alternative molecular basis data available.
BP6 No reputable source has classified this variant as benign or likely benign. ClinVar classification is Uncertain significance from a single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar variation 1708311: classification Uncertain significance. No benign classification from any source.
Sources
PS5 This variant has not been asserted as pathogenic by a reputable source (ClinGen expert panel, clinical practice guideline, or validated functional study). ClinVar classification is Uncertain significance, single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Uncertain significance (criteria provided
- single submitter). No expert panel or authoritative source has asserted pathogenicity.
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient data to assess PP2. EIF1AX is an X-linked gene with recurrent missense mutations in the NTT domain. However, no gene-specific missense constraint metrics (z-score, HCI prior) are available for this gene. PP2 requires a low rate of benign missense variation and evidence that missense variants are a common disease mechanism — while the literature supports a gain-of-function missense mechanism, population-level constraint data are lacking. Details ▾Hide ▴
Evidence considered
- HCI prior not available for EIF1AX. No REVEL score. Missense constraint metrics not computed in evidence brief.
Still missing
- Gene-level missense constraint data (z-score
- missense depletion metrics) not available
- manual assessment of ClinGen/gnomAD constraint required.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable. NM_001412.4:c.17G>T is a missense variant (p.Gly6Val) and does not meet the null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required by the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- PVS1 variant assessment classified this as bucket 'other'
- apply_generic_pvs1_framework=false.
Sources
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. EIF1AX is X-linked and associated disease is not recessive. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies only to non-repeat in-frame deletions/insertions or stop-loss variants causing protein length change. This variant is a single nucleotide substitution producing a missense change. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies only to in-frame deletions/insertions in repetitive regions. This variant is a single nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous variants with no predicted splicing impact. NM_001412.4:c.17G>T is a missense variant (p.Gly6Val). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- EIF1AX
- Transcript
- NM_001412.4
- Coding (HGVS c.)
- NM_001412.4:c.17G>T
- Protein (HGVS p.)
- NP_001403.1:p.(Gly6Val)
- GRCh38
- chrX:20138622 C>A
- GRCh37
- chrX:20156740 C>A
- ClinVar
- 1708311
- COSMIC
- COSV105919481
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
- -0.263
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign effect (score -0.263, below the deleterious threshold) and SpliceAI predicts no splicing alteration (max delta score = 0.00). REVEL is not available for this variant. Details ▾Hide ▴
Evidence considered
- BayesDel score: -0.263 (benign range). SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
bayesdelspliceai ↗
PP3 In silico tools do not support a deleterious effect. BayesDel score is -0.263 (benign-leaning), SpliceAI predicts no splicing impact (max delta score = 0.00), and REVEL is unavailable. Multiple lines of computational evidence do not agree on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- BayesDel score: -0.263 (benign range). SpliceAI max delta: 0.00 (no splice impact). REVEL: not available.
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous variants with no predicted splicing impact. NM_001412.4:c.17G>T is a missense variant (p.Gly6Val). 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 = -0.263094.
3 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 28594900 ↗Systematic genomic and translational efficiency studies of uveal melanoma.Characterized EIF1AX N-terminal tail (NTT) mutations in uveal melanoma. Identified G6D as a recurrent missense change at Gly6 in the 92.1 cell line. Functional studies showed EIF1AX NTT mutants are gain-of-function, with altered polysome profiles and impaired regulation of ribosomal protein translation. NM_001412.4:c.17G>T (p.Gly6Val) was not specifically identified.→ PM1 Does not name this variant
Source detail
We also identified a homozygous G→A mutation at the start of exon 2 in a single established UM cell line (92.1)… demonstrated faithful transcription of the G6D missense mutation, without evidence for altered mRNA splicing or wild type allele expression.
Location Results: 'Mutant and wild type EIF1AX play essential roles in uveal melanoma cells'; Figure 2A; S4 Fig
Context Uveal melanoma cell lines (92.1, Omm2.3, Omm1); lentiviral shRNA knockdown; polysome profiling; RNAseq
-
PMID 30420357 ↗Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes.Tested seven cancer-associated EIF1AX NTT mutants (G6D, G9D, G9R, G8RG9R, K10E, R13H, G15D) in MEFs and HEK293T cells. G6D reduced binding to ribosomal protein Rps10 and enhanced scanning of long 5'UTR-containing cell cycle genes. NM_001412.4:c.17G>T (p.Gly6Val) was not specifically tested.→ PM1 Does not name this variant
Source detail
Rps10 all mutants G6D, G9D/R13H and K10E bound less efficiently.
Location Results: 'Cancer associated eIF1A NTT mutants primarily enhance translation of long 5'UTR mRNAs' and 'NTT mutants are defective in A-site Rps10 and Rps3 binding'; Figures 7-8; Methods: Plasmids section
Context MEFs, HEK293T cells; dual-luciferase reporter gene assays; polysome profiling; His-pull down binding assays with recombinant Rps3 and Rps10
Other recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. Does not discuss NM_001412.4:c.17G>T, p.Gly6Val, EIF1AX, or any specific variant relevant to this case.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
1 Uncertain significance
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/1708311/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-20156740-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-20138622-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-20138622-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001412.4%3Ac.17G%…
- OncoKB ↗www.oncokb.org/gene/EIF1AX/G6V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=144402837
- 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 as Uncertain significance (1 clinical laboratory). (ClinVarID = 1708311)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.263094.
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; COSV105919481, n = 2 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.