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EIF1AXc.338-1G>CLikely pathogenic
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Variant interpretation report

EIF1AX c.338-1G>C, p.?

NM_001412.4:c.338-1G>C NP_001403.1:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong

NM_001412.4:c.338-1G>C is a canonical ±1 splice acceptor variant affecting intron 5 of EIF1AX. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical splice variants in genes where loss of function is an established disease mechanism are assigned PVS1. EIF1AX germline loss of function is supported as a disease mechanism in uveal melanoma predisposition based on targeted literature review. The MANE Select transcript NM_001412.4 is biologically relevant. No evidence of nonsense-mediated decay escape, alternative splicing of the affected exon, or population LoF enrichment was identified. PVS1 is applied at strong strength given the limited but positive germline LoF evidence base for this gene.

PM2Moderate
PM2 · moderate

NM_001412.4:c.338-1G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP rules, absence from large population databases supports PM2 at moderate strength (allele frequency < 0.1%).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 moderate; combination = 1 strong + 1 moderate, which maps to Likely Pathogenic.

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
0.680 maximum delta

Recorded SpliceAI maximum delta score: 0.680. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV65450922, n = 3 times).

Context only COSMIC ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 2 met · 17 not met · 0 not assessed · 7 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

NM_001412.4:c.338-1G>C is a canonical ±1 splice acceptor variant in intron 5 of EIF1AX, a gene in which loss of function is supported as a germline disease mechanism in uveal melanoma predisposition. Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at strong strength.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, satisfying PM2 at moderate strength.

SpliceAI predicts a splice-altering effect (max delta score 0.68, acceptor loss). This computational evidence is already accounted for in PVS1 and is not separately applied as PP3 per PMC6185798 guidance against double-counting splice prediction evidence.

No de novo data (PS2/PM6), no functional studies (PS3/BS3), no case-control data (PS4), no segregation data (PP1/BS4), and no patient phenotype information (PP4) are available for this variant. These criteria remain unmet.

ClinVar variation ID 4484109 has zero submissions, no classification, and no review status. PP5 and BP6 cannot be applied.

The variant has been observed in 3 somatic tumor samples in COSMIC (COSV65450922). Somatic occurrence does not independently satisfy germline criteria but is consistent with a role in tumorigenesis.

The only associated publication (PMID:31275557) describes a pan-cancer splicing mutation repository but does not include NM_001412.4:c.338-1G>C in its dataset. No publication provides variant-specific evidence for any criterion.

Overall classification: Likely Pathogenic. The combination of PVS1 (strong) and PM2 (moderate) satisfies the generic ACMG/AMP 2015 threshold for Likely Pathogenic (1 strong + 1 moderate).

Met · 2

PVS1 StrongNM_001412.4:c.338-1G>C is a canonical ±1 splice acceptor variant affecting intron 5 of EIF1AX. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical splice variants in genes where loss of function is an established disease mechanism are assigned PVS1. EIF1AX germline loss of function is supported as a disease mechanism in uveal melanoma predisposition based on targeted literature review. The MANE Select transcript NM_001412.4 is biologically relevant. No evidence of nonsense-mediated decay escape, alternative splicing of the affected exon, or population LoF enrichment was identified. PVS1 is applied at strong strength given the limited but positive germline LoF evidence base for this gene. Details ▾Hide ▴
Evidence considered
  • Canonical ±1
  • 2 splice acceptor variant (c.338-1G>C
  • intron 5) under PMC6185798
  • EIF1AX LoF is supported as a germline disease mechanism (pvs1_gene_gate: eligible)
  • NM_001412.4 is MANE Select transcript
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada
Still missing
  • EIF1AX germline LoF disease mechanism is based on a limited number of publications in uveal melanoma predisposition
  • no official CSPEC/VCEP framework exists
  • Exact exon and predicted protein consequence could not be determined (protein consequence is p.?)
  • Confirmation of aberrant splicing by RNA studies would strengthen this criterion
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentgnomad_v2 ↗gnomad_v4 ↗
PM2 ModerateNM_001412.4:c.338-1G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP rules, absence from large population databases supports PM2 at moderate strength (allele frequency < 0.1%). 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 ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. No publications or ClinVar submissions report de novo occurrence of NM_001412.4:c.338-1G>C. Details ▾Hide ▴
Still missing
  • No parental testing or de novo confirmation data available
PS3 No variant-specific functional data are available for NM_001412.4:c.338-1G>C. PMID:31275557 describes a pan-cancer splicing mutation repository but does not include this specific variant. No in vitro or in vivo functional studies of this splice variant were identified in the literature. Domain-level inference from the EIF1AX somatic cancer literature does not satisfy PS3 requirements for a germline variant. Details ▾Hide ▴
Still missing
  • No RNA studies confirming aberrant splicing
  • No functional assays performed on this variant
PS4 No case-control or prevalence data are available. ClinVar variation ID 4484109 has zero submissions with extractable clinical classifications. COSMIC reports this variant in 3 somatic tumor samples, but somatic occurrence does not meet PS4 requirements which assess enrichment in affected individuals versus controls for germline disease. Details ▾Hide ▴
Evidence considered
  • ClinVar record (4484109): 0 submissions with extractable classifications
  • COSMIC: 3 somatic occurrences only — insufficient for germline PS4
Still missing
  • No germline case reports or cohort data
Sources
clinvar ↗
PM1 This variant is a canonical splice site (c.338-1G>C, intron 5 acceptor) and does not fall within a characterized functional domain or mutational hotspot for missense alterations. While EIF1AX somatic missense mutations cluster in specific regions in uveal melanoma, the affected splice position itself has not been established as a mutational hotspot. The variant is not listed at cancerhotspots.org and no domain-specific data support PM1 for this splice position. Details ▾Hide ▴
Still missing
  • No domain-level or hotspot data specific to this splice position
PM6 No de novo data are available for NM_001412.4:c.338-1G>C. No publications or ClinVar submissions report de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
  • No de novo testing performed
PP1 No segregation data are available for this variant. No family studies or co-segregation analyses of NM_001412.4:c.338-1G>C with disease have been reported. Details ▾Hide ▴
Still missing
  • No family segregation data
PP4 No patient phenotype information is available for this variant. No clinical case data with detailed phenotypic description were identified in ClinVar submissions or the literature. Details ▾Hide ▴
Still missing
  • No proband phenotype data available
PP5 ClinVar variation ID 4484109 has zero submissions, no classification, and no review status (no star rating). Under the PP5 rule, a 3-star expert panel classification is required for supporting strength. With no classification and zero submissions, PP5 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ClinVar 4484109: 0 submissions
  • no classification
  • no review status
Still missing
  • No expert panel or multi-submitter ClinVar classification
Sources
clinvar ↗
BA1 BA1 requires an allele frequency > 1% in population databases. NM_001412.4:c.338-1G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires an allele frequency > 0.3% in population databases (non-VCEP generic threshold). NM_001412.4:c.338-1G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No evidence is available regarding observation of this variant in healthy adults. The variant is absent from population databases (gnomAD), so it has not been observed in apparently healthy individuals. Details ▾Hide ▴
Still missing
  • No data on observation in healthy adults
BS3 No functional studies demonstrating a neutral effect of NM_001412.4:c.338-1G>C have been identified. SpliceAI predicts a splice-altering effect (max delta 0.68), which is inconsistent with a benign functional assessment. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts splice-altering effect (delta 0.68) — contradicts benign functional assessment
Still missing
  • No RNA or functional studies demonstrating normal splicing
Sources
spliceai ↗
BS4 No segregation data in affected families are available. No evidence that this variant does not segregate with disease has been reported. Details ▾Hide ▴
Still missing
  • No segregation data
BP2 No evidence of observation in trans with a pathogenic variant is available. EIF1AX is X-linked, which complicates standard BP2 assessment. No clinical or population data demonstrate co-occurrence patterns. Details ▾Hide ▴
Still missing
  • No data on co-occurrence with pathogenic variants
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene product. SpliceAI predicts a splice-altering effect (max delta 0.68, acceptor loss 0.68), and BayesDel (0.25) is borderline. Computational evidence does not support a benign interpretation; it is consistent with a deleterious splicing effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta 0.68 — predicts splice alteration
  • inconsistent with BP4
  • BayesDel 0.25 — borderline
  • does not independently support benign effect
Sources
spliceai ↗bayesdel
BP5 No evidence is available that this variant has been observed in a case with an alternative molecular basis for disease. No clinical data with comprehensive genetic workup were identified. Details ▾Hide ▴
Still missing
  • No data on cases with alternative molecular diagnoses
BP6 ClinVar variation ID 4484109 has zero submissions, no classification, and no review status (no star rating). Under the BP6 rule, a 3-star expert panel benign classification would be required for supporting strength. With no classification, BP6 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ClinVar 4484109: 0 submissions
  • no classification
  • no review status
Still missing
  • No expert panel or multi-submitter ClinVar classification
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a nucleotide change at the same position as a known pathogenic variant where both result in the same amino acid change. This is a canonical splice site variant, not a coding change, and there is no same-position pathogenic comparator. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 is defined for a novel missense change at an amino acid residue where a different pathogenic missense change has been previously reported. This variant is a canonical splice site variant, not a missense change. The pm5_candidates.json pipeline could not establish same-residue semantics and found zero comparator variants. PM5 does not apply. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 is defined for missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This is a canonical splice site variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AUnder ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 for canonical splice variants when both are based on the same splice-effect prediction evidence. SpliceAI predicts a splice-altering effect (max delta 0.68, acceptor loss 0.68), which is the same evidence type underpinning PVS1. BayesDel score (0.25) is borderline and does not independently support PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.68 — splice-altering prediction already accounted for in PVS1
  • BayesDel 0.25 — borderline
  • not independently supportive
Sources
spliceai ↗bayesdelpvs1_generic_framework ↗
BP1 N/ABP1 is defined for a missense variant in a gene where primarily truncating variants cause disease. This variant is a canonical splice site variant predicted to cause a null (truncating) effect, which is consistent with the loss-of-function disease mechanism for EIF1AX. BP1 does not apply. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 is defined for synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. This is a canonical splice site variant with a predicted splice-altering effect (SpliceAI delta 0.68); BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is defined for a novel missense change at an amino acid residue where a different pathogenic missense has been seen. This is a canonical splice site variant and PS5 does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
EIF1AX
Transcript
NM_001412.4
Coding (HGVS c.)
NM_001412.4:c.338-1G>C
Protein (HGVS p.)
NP_001403.1:p.?
GRCh38
chrX:20130608 C>G
GRCh37
chrX:20148726 C>G
ClinVar
4484109
COSMIC
COSV65450922

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 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 -1 bp
0.680
SpliceAI acceptor gainat -37 bp
0.190
SpliceAI donor lossat -92 bp
0.000
SpliceAI donor gainat -96 bp
0.000
Pangolin splice lossmagnitude shown
-0.850
Pangolin splice gain
0.110

Other predictors

REVEL
Not available
BayesDel
0.250

How the predictions were used

BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene product. SpliceAI predicts a splice-altering effect (max delta 0.68, acceptor loss 0.68), and BayesDel (0.25) is borderline. Computational evidence does not support a benign interpretation; it is consistent with a deleterious splicing effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta 0.68 — predicts splice alteration
  • inconsistent with BP4
  • BayesDel 0.25 — borderline
  • does not independently support benign effect
Sources
spliceai ↗bayesdel
PP3 N/AUnder ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 for canonical splice variants when both are based on the same splice-effect prediction evidence. SpliceAI predicts a splice-altering effect (max delta 0.68, acceptor loss 0.68), which is the same evidence type underpinning PVS1. BayesDel score (0.25) is borderline and does not independently support PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.68 — splice-altering prediction already accounted for in PVS1
  • BayesDel 0.25 — borderline
  • not independently supportive
Sources
spliceai ↗bayesdelpvs1_generic_framework ↗
BP7 N/ABP7 is defined for synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. This is a canonical splice site variant with a predicted splice-altering effect (SpliceAI delta 0.68); BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.68). BayesDel score = 0.249774.

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

  • Pan-cancer repository of validated natural and cryptic mRNA splicing mutations.
    Shirley BC et al. · 2018
    Describes a pan-cancer repository of validated natural and cryptic mRNA splicing mutations using information theory-based analyses. NM_001412.4:c.338-1G>C was not identified in the full text. EIF1AX is not mentioned in this paper.
    Does not name this variant
    PMID 31275557 ↗

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 0.680 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC 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 has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4484109)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.68). BayesDel score = 0.249774.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV65450922, n = 3 times).