NM_001412.4:c.338-1G>C

EIF1AX · NP_001403.1:p.? · NM_001412.4

GRCh37: chrX:20148726 C>G · GRCh38: chrX:20130608 C>G

Gene: EIF1AX Transcript: NM_001412.4

Final call

Likely Pathogenic

PVS1 strong PM2 moderate

Variant details

Gene

EIF1AX

Transcript

NM_001412.4

Protein

NP_001403.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment gnomad_v2 gnomad_v4
PS1	N/A	PS1 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.
PS2	Not met	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.
PS3	Not met	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.
PS4	Not met	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.	clinvar
PS5	N/A	PS5 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.
PM1	Not met	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.
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 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.
PM6	Not met	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.
PP1	Not met	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.
PP2	N/A	PP2 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.
PP3	N/A	Under 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.	spliceai bayesdel pvs1_generic_framework
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.
BS3	Not met	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.	spliceai
BS4	Not met	No segregation data in affected families are available. No evidence that this variant does not segregate with disease has been reported.
BP1	N/A	BP1 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.
BP2	Not met	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.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.