NM_001128849.1:c.1813-2A>T

SMARCA4 · NP_001122321.1:p.? · NM_001128849.1

GRCh37: chr19:11113703 A>T · GRCh38: chr19:11003027 A>T

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2 in SMARCA4, a gene where loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) [PVS1, very strong].

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0%), consistent with PM2 at moderate strength under generic ACMG/AMP 2015 criteria.

SpliceAI predicts a strong splice-disrupting effect (max delta = 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score (0.66), but PP3 is not stacked with PVS1 per ClinGen SVI guidance (PMC6185798) to avoid double-counting the same splice-effect evidence.

This variant is absent from ClinVar and has not been reported in any publication; no external classification, functional data, segregation data, or de novo observations are available.

Under generic ACMG/AMP 2015 combination rules, one very strong (PVS1) and one moderate (PM2) criterion are sufficient for a Pathogenic classification. However, transcript version discrepancy (NM_001128849.1 vs NM_001128849.3) and absence of RNA-confirmed splicing impact warrant confirmatory review.

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_001128849.1:c.1813-2A>T is a canonical splice acceptor variant (position -2) in SMARCA4, a gene for which loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants are treated as null variants and qualify for PVS1 at very strong strength when the gene LoF disease mechanism is confirmed.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same codon predicted to produce the same missense change. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant, not a missense substitution, so PS1 does not apply.
PS2	Not assessed	No de novo data are available for this variant. No published studies or database entries report de novo occurrence of NM_001128849.1:c.1813-2A>T with confirmed parentage.
PS3	Not assessed	No well-established in vitro or in vivo functional studies have been identified for NM_001128849.1:c.1813-2A>T. No publications report functional characterization of this specific splice variant.
PS4	Not assessed	No case-control or cohort data are available to assess whether the prevalence of NM_001128849.1:c.1813-2A>T is significantly increased in affected individuals versus controls.
PS5	Not assessed	No reputable source (e.g., clinical laboratory, research consortium) has reported NM_001128849.1:c.1813-2A>T as pathogenic. The variant is absent from ClinVar.	clinvar
PM1	Not assessed	No mutational hotspot or critical functional domain data are available specifically for the c.1813-2 splice acceptor position in SMARCA4. Hotspot analysis did not identify this position as a recurrently mutated residue or splice site.
PM2	Met	NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), consistent with PM2 under generic ACMG/AMP 2015 criteria (allele frequency <0.1% in population databases).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to missense variants where a different amino acid substitution at the same residue has been established as pathogenic. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant with an unknown protein consequence (p.?), and no residue-level comparator can be determined.	pm5_candidates
PM6	Not assessed	No de novo observation of NM_001128849.1:c.1813-2A>T has been reported. No published studies or database entries describe a de novo occurrence of this variant without confirmed parentage.
PP1	Not assessed	No co-segregation data are available for NM_001128849.1:c.1813-2A>T with disease in multiple affected family members.
PP2	Not assessed	PP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_001128849.1:c.1813-2A>T is a canonical splice variant, not a missense change, so PP2 is not directly applicable.
PP3	N/A	Under ClinGen SVI PVS1 guidance (PMC6185798), PP3 (in silico prediction of pathogenicity) should not be stacked with PVS1 when the in silico evidence supports the same splice-effect prediction already captured by PVS1. SpliceAI predicts a deleterious effect (max delta 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score (0.66), but this evidence is redundant with PVS1 and is not independently applied to avoid double-counting.	spliceai bayesdel pvs1_generic_framework
PP4	Not assessed	No patient phenotype or clinical history is available for NM_001128849.1:c.1813-2A>T. PP4 requires the variant to be found in a patient with a phenotype and family history highly specific for a disease with a single genetic etiology.
PP5	Not assessed	No reputable source has reported NM_001128849.1:c.1813-2A>T as pathogenic. The variant is absent from ClinVar, and no clinical laboratory or expert panel classification is available.	clinvar
BA1	Not met	NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BS1 threshold of >0.3% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of NM_001128849.1:c.1813-2A>T in healthy adults with full penetrance expected at an early age. No population or clinical cohort data address this criterion.
BS3	Not assessed	No well-established functional studies have been performed for NM_001128849.1:c.1813-2A>T demonstrating no deleterious effect on splicing or protein function.
BS4	Not assessed	No segregation data are available to assess whether NM_001128849.1:c.1813-2A>T lacks segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. NM_001128849.1:c.1813-2A>T is a canonical splice variant, not a missense substitution, so BP1 does not apply.
BP2	Not assessed	No data are available regarding observation of NM_001128849.1:c.1813-2A>T in trans with a known pathogenic variant in SMARCA4. No phase information is available.
BP4	Not met	In silico predictions are consistent with a deleterious effect. SpliceAI predicts strong splice disruption (max delta = 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score of 0.66. These results do not support BP4, which requires multiple lines of computational evidence suggesting no impact.	spliceai bayesdel
BP5	Not assessed	No case has been reported where NM_001128849.1:c.1813-2A>T is found in an individual with an alternative molecular basis for disease. No alternative causative variants have been documented in carriers of this variant.
BP6	Not assessed	No reputable source has reported NM_001128849.1:c.1813-2A>T as benign or likely benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2, not a synonymous coding variant, so BP7 does not apply.

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