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).1 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.2 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).3 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.4 Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), PVS1 (Very Strong) plus PM2 (Moderate) yields a classification of Likely Pathogenic.5
SMARCA4
Final classification
Likely Pathogenic
SMARCA4 c.1944-1G>T · p.?
SMARCA4
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).
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 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
SMARCA4 c.1944-1G>T
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_gene_contextpvs1_generic_framework ↗
2
pvs1_variant_assessmentspliceai ↗pvs1_generic_framework ↗
4
pvs1_variant_assessment
5
generic_acmg_combination_rules
Gene diagram
· NM_001128849.1 · variants mapped to exon structure
SMARCA4
NM_001128849.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 16 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
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).
Canonical splice acceptor variant at intron 12 position -1 (c.1944-1G>T)SpliceAI delta score 0.99 with acceptor loss prediction 0.99SMARCA4 loss of function is an established disease mechanism for RTPS2
✓
PM2
moderate
Pathogenic
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%).
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No well-established functional studies were identified that directly assay NM_001128849.1:c.1944-1G>T.
PS4
No case-control or cohort data are available to assess enriched prevalence of this variant in affected individuals.
PM1
This variant is located at a canonical splice acceptor site (intron 12), not within a recognized SMARCA4 functional domain or mutational hotspot.
PM6
No confirmed de novo observation of NM_001128849.1:c.1944-1G>T has been reported.
PP1
No cosegregation data are available for this variant.
PP4
No phenotype or family history data specific to this variant are available for assessment.
PP5
This variant is absent from ClinVar and has not been classified by any reputable source.
Benign
BA1
This variant is absent from gnomAD (allele frequency 0%); it does not reach the BA1 threshold of >1%.
BS1
This variant is absent from gnomAD (allele frequency 0%); it does not reach the BS1 benign threshold of >0.3%.
BS2
No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3
No well-established functional studies are available showing no deleterious effect for NM_001128849.1:c.1944-1G>T.
BS4
No cosegregation data are available to assess lack of segregation with disease.
BP2
No data are available to assess observation in trans with a pathogenic dominant variant.
BP4
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.
BP5
No cases have been reported in which this variant was found together with an alternate molecular basis for disease.
N/A · 10
PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links