Variant classification summary

NM_001128849.1:c.1944-1G>T

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

GRCh37: chr19:11114015 G>T · GRCh38: chr19:11003339 G>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

1

NM_001128849.1:c.1944-1G>T is a canonical splice acceptor variant (c.1944-1G>T, intron 12) in SMARCA4, a gene for which loss of function is an established disease mechanism for rhabdoid tumor predisposition syndrome type 2 (RTPS2).

2

Under the ClinGen SVI PVS1 decision tree (PMC6185798), canonical ±1,2 splice site variants receive PVS1 at very strong strength when LOF is a confirmed disease mechanism. SpliceAI predicts a high-impact splice alteration (delta score 0.99, acceptor loss 0.99), consistent with disruption of the intron 12 splice acceptor.

3

The variant is absent from all queried population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion at moderate strength (<0.1% allele frequency threshold).

4

PP3 is not applied because the splice prediction evidence (SpliceAI) is already accounted for in the PVS1 assessment; the ClinGen SVI PVS1 guidance explicitly prohibits stacking PP3 for the same splice-effect evidence.

5

Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), PVS1 (Very Strong) plus PM2 (Moderate) yields a classification of Likely Pathogenic.

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	This variant alters the canonical splice acceptor site at position -1 of intron 12 (c.1944-1G>T). SMARCA4 loss of function is an established disease mechanism for rhabdoid tumor predisposition syndrome type 2 (RTPS2). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice site variants are eligible for PVS1 at very strong weight when LOF is a confirmed disease mechanism. SpliceAI predicts a high-impact splice alteration (delta score 0.99, acceptor loss 0.99).	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	This is a splice site variant with an indeterminate protein consequence (p.?); no same-amino-acid pathogenic comparator can be established.
PS2	Not assessed	No de novo data are available for this variant.
PS3	Not assessed	No well-established functional studies were identified that directly assay NM_001128849.1:c.1944-1G>T.
PS4	Not assessed	No case-control or cohort data are available to assess enriched prevalence of this variant in affected individuals.
PS5	N/A	This is a splice site variant without a defined protein-level residue; PS5 requires a pathogenic missense comparator at the same residue, which cannot be established.
PM1	Not assessed	This variant is located at a canonical splice acceptor site (intron 12), not within a recognized SMARCA4 functional domain or mutational hotspot.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the PM2 threshold for extremely low population frequency (<0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	This is a canonical splice site variant with no defined protein residue (p.?); PM5 requires a known pathogenic missense variant at the same amino acid position.	pm5_candidates
PM6	Not assessed	No confirmed de novo observation of NM_001128849.1:c.1944-1G>T has been reported.
PP1	Not assessed	No cosegregation data are available for this variant.
PP2	N/A	This is a splice site variant, not a missense variant; PP2 is defined for missense variants in genes with a low rate of benign missense variation.
PP3	N/A	Per ClinGen SVI PVS1 guidance (PMC6185798), PP3 must not be stacked on top of PVS1 for the same splice-effect prediction evidence. The SpliceAI delta score of 0.99 is already accounted for in the PVS1 assessment of canonical splice disruption.	pvs1_variant_assessment
PP4	Not assessed	No phenotype or family history data specific to this variant are available for assessment.
PP5	Not assessed	This variant is absent from ClinVar and has not been classified by any reputable source.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this is a single-nucleotide substitution at a splice site.
PM3	N/A	PM3 applies to recessive disorders with a second pathogenic variant in trans; SMARCA4-associated disease is dominant and no trans data are available.
PM4	N/A	PM4 applies to protein-length-altering variants; this is a canonical splice site variant assessed under PVS1.
BA1	Not met	This variant is absent from gnomAD (allele frequency 0%); it does not reach the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD (allele frequency 0%); it does not reach the BS1 benign threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not assessed	No well-established functional studies are available showing no deleterious effect for NM_001128849.1:c.1944-1G>T.
BS4	Not assessed	No cosegregation data are available to assess lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are a known disease mechanism; this is a canonical splice site variant, not a missense variant.
BP2	Not assessed	No data are available to assess observation in trans with a pathogenic dominant variant.
BP4	Not met	Multiple computational predictors indicate a deleterious effect: SpliceAI predicts strong splice disruption (delta score 0.99, acceptor loss 0.99) and BayesDel scores 0.66, consistent with a deleterious rather than benign prediction.	spliceai bayesdel
BP5	Not assessed	No cases have been reported in which this variant was found together with an alternate molecular basis for disease.
BP6	N/A	This variant is absent from ClinVar; no reputable source has classified it as benign.
BP7	N/A	BP7 applies to silent variants with no predicted splice impact; NM_001128849.1:c.1944-1G>T is a canonical splice site variant with SpliceAI delta score 0.99, indicating a strong predicted splice alteration.	spliceai

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.