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EIF1AXc.5C>TUncertain significance
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Variant interpretation report

EIF1AX c.5C>T, p.(Pro2Leu)

NM_001412.4:c.5C>T NP_001403.1:p.(Pro2Leu) 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.

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 codon 2 (p.Pro2Leu) in EIF1AX, a residue within a statistically significant mutational hotspot identified by cancerhotspots.org. EIF1AX is a well-established driver gene in uveal melanoma, and the N-terminal region encompassing codon 2 is critical for translation initiation function. The variant is completely absent from gnomAD, consistent with a functionally constrained residue.

PM2Moderate
PM2 · moderate

This variant is completely absent from population databases. gnomAD v4.1 reports 0 alleles in 1,155,341 alleles (AF=0.00%), gnomAD v2.1 reports absence, and gnomAD Canada reports absence. The allele frequency of 0% is well below the PM2 threshold of <0.1%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.368928 (well below the deleterious threshold of 0.27), integrating conservation, evolutionary, and biochemical features. SpliceAI predicts no splice impact (max delta score 0.00).

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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
7 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV65451032, n = 7 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: 3 met · 20 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The variant is located at codon 2 (p.Pro2Leu), a statistically significant mutational hotspot residue in EIF1AX, a well-established driver gene in uveal melanoma (PM1_moderate).

The variant is completely absent from gnomAD v4.1 (0/1,155,341 alleles), gnomAD v2.1, and gnomAD Canada, meeting the PM2 criterion for absence from population databases (PM2_moderate).

BayesDel predicts a benign score of -0.368928, and SpliceAI predicts no splice impact (max delta 0.00), providing multiple lines of computational evidence against a damaging effect (BP4_supporting).

No functional studies, de novo reports, segregation data, or ClinVar classifications exist for this variant. PS3, PS2, PP1, PP5, and BS3 are not met. PVS1, PM5, and BP7 are not applicable to this missense variant.

Met · 3

PM1 ModerateThe variant is located at codon 2 (p.Pro2Leu) in EIF1AX, a residue within a statistically significant mutational hotspot identified by cancerhotspots.org. EIF1AX is a well-established driver gene in uveal melanoma, and the N-terminal region encompassing codon 2 is critical for translation initiation function. The variant is completely absent from gnomAD, consistent with a functionally constrained residue. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: P2 residue in a statistically significant hotspot
  • COSMIC: 7 somatic observations at this position
  • OncoKB: Likely Oncogenic
  • gnomAD v4.1: 0/1
  • 155
  • 341 alleles.
Sources
gnomad_v4 ↗oncokb ↗
PM2 ModerateThis variant is completely absent from population databases. gnomAD v4.1 reports 0 alleles in 1,155,341 alleles (AF=0.00%), gnomAD v2.1 reports absence, and gnomAD Canada reports absence. The allele frequency of 0% is well below the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0/1
  • 155
  • 341 alleles (AF=0.00%)
  • gnomAD v2.1: absent
  • gnomAD Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.368928 (well below the deleterious threshold of 0.27), integrating conservation, evolutionary, and biochemical features. SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.368928 (benign
  • integrating 46 features)
  • SpliceAI: max delta 0.00 (no predicted splice alteration).
Still missing
  • REVEL score unavailable for independent corroboration.
Sources
bayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 No prior pathogenic variant with the same amino acid change (P2L) has been established in ClinVar or the literature. Without a previously classified pathogenic comparator at this residue with the same change, PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for this variant or any P2L change in EIF1AX.
Sources
clinvar ↗
PS2 No de novo occurrence data with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available for this variant.
PS3 No well-established in vitro or in vivo functional studies directly testing this variant were identified. OncoKB annotates the variant as Likely Oncogenic in a somatic context but provides no curated PMIDs or experimental data for independent review. COSMIC reports 7 somatic observations without functional characterization. The cancerhotspots.org residue-level significance constitutes domain-level (PM1) evidence, not variant-specific functional evidence for PS3. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Likely Oncogenic (somatic context
  • no PMIDs)
  • COSMIC COSV65451032: 7 somatic observations
  • no functional annotation.
Still missing
  • No variant-specific functional studies (e.g.
  • luciferase reporter
  • cellular transformation assay
  • or in vivo tumorigenesis model) are available in the case materials.
Sources
oncokb ↗
PS4 No case-control data comparing variant prevalence in affected versus unaffected individuals is available. Details ▾Hide ▴
Still missing
  • No case-control or cohort enrichment data available.
PM6 No de novo occurrence data (without confirmed paternity and maternity) is available for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No cosegregation data in affected family members is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP2 Insufficient constraint data to determine whether EIF1AX has a low rate of benign missense variation. No gnomAD missense Z-score or observed/expected ratio is available. HCI prior is not supported for this gene. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported
  • REVEL: not available
  • no gnomAD constraint metrics retrieved.
Still missing
  • gnomAD gene constraint metrics (missense Z-score
  • o/e) not available for formal PP2 assessment.
PP3 Computational evidence does not support a deleterious effect. BayesDel predicts a benign score of -0.368928 (deleterious threshold >0.27). REVEL is not available. SpliceAI predicts no splice impact (max delta 0.00), which is neutral rather than supportive of pathogenicity. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.368928 (benign)
  • REVEL: not found
  • SpliceAI: max delta 0.00.
Still missing
  • REVEL score unavailable for chromosome X.
Sources
bayesdelspliceai ↗
PP4 No patient phenotype or family history data is available to assess specificity for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No phenotype or clinical data provided for this case.
PP5 This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. No expert panel or clinical laboratory has classified this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar: absent
  • no germline classification from any source.
Sources
clinvar ↗
BA1 The variant allele frequency is 0.00% in gnomAD v4.1 (0/1,155,341 alleles), far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00% (0/1
  • 155
  • 341 alleles).
Sources
gnomad_v4 ↗
BS1 The variant allele frequency is 0.00% in gnomAD v4.1, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00% (0/1
  • 155
  • 341 alleles).
Sources
gnomad_v4 ↗
BS2 No data on observation in healthy adult individuals for a fully penetrant disorder is available. Details ▾Hide ▴
Still missing
  • No healthy control observation data available.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant are available. Details ▾Hide ▴
Still missing
  • No functional studies demonstrating a benign effect exist.
BS4 No segregation data in affected family members is available to assess lack of segregation. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP1 EIF1AX is an oncogene in which missense variants are the primary established disease mechanism, not a gene where primarily truncating variants cause disease. Germline literature review (PMID:39344744) explicitly reports that EIF1AX lacked pathogenic germline variants in a uveal melanoma cohort, and the known oncogenic mechanism is gain-of-function via missense mutations in the N-terminal domain. Details ▾Hide ▴
Evidence considered
  • EIF1AX is a known oncogene with missense driver mutations
  • truncating variants are not the primary disease mechanism. PMID:39344744 reports no pathogenic germline EIF1AX variants in 270 Finnish UM patients.
Sources
pvs1_gene_context
BP2 No data on observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, is available. Details ▾Hide ▴
Still missing
  • No phase data available.
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
BP6 This variant is absent from ClinVar and has not been reported as benign by any reputable source. Details ▾Hide ▴
Evidence considered
  • ClinVar: absent
  • no benign classification from any source.
Sources
clinvar ↗
PS5 This variant has not been reported as pathogenic by a reputable source where the underlying evidence is unavailable for independent evaluation. The variant is absent from ClinVar and no other germline classification source has assessed it. Details ▾Hide ▴
Evidence considered
  • ClinVar: no submissions
  • no classification from any submitter.
Sources
clinvar ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution (c.5C>T, p.Pro2Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense variants. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution at codon 2
  • PVS1 variant bucket classified as 'other'
  • generic PVS1 framework criteria not met.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo comparator missense variant at codon 2 with a different amino acid change has been established as pathogenic. PM5 requires a different missense change at the same residue that is already classified as pathogenic. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero same-residue comparator variants in ClinVar.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (c.5C>T, p.Pro2Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant class: missense substitution.

Identifiers

Gene
EIF1AX
Transcript
NM_001412.4
Coding (HGVS c.)
NM_001412.4:c.5C>T
Protein (HGVS p.)
NP_001403.1:p.(Pro2Leu)
GRCh38
chrX:20141636 G>A
GRCh37
chrX:20159754 G>A
COSMIC
COSV65451032

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…
gnomAD v4.1 0 / 1,155,341 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,155,341 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1155341 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/55330 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
-0.369

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.368928 (well below the deleterious threshold of 0.27), integrating conservation, evolutionary, and biochemical features. SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.368928 (benign
  • integrating 46 features)
  • SpliceAI: max delta 0.00 (no predicted splice alteration).
Still missing
  • REVEL score unavailable for independent corroboration.
Sources
bayesdelspliceai ↗
PP3 Computational evidence does not support a deleterious effect. BayesDel predicts a benign score of -0.368928 (deleterious threshold >0.27). REVEL is not available. SpliceAI predicts no splice impact (max delta 0.00), which is neutral rather than supportive of pathogenicity. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.368928 (benign)
  • REVEL: not found
  • SpliceAI: max delta 0.00.
Still missing
  • REVEL score unavailable for chromosome X.
Sources
bayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.5C>T, p.Pro2Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant class: missense substitution.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.368928.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 0 / 1,155,341 recorded alleles 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

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1155341 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/55330 alleles, homozygotes = 0).

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 = 0.00). BayesDel score = -0.368928.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65451032, n = 7 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.