NM_001128849.1:c.2764T>A

SMARCA4 · NP_001122321.1:p.(Trp922Arg) · NM_001128849.1

GRCh37: chr19:11132548 T>A · GRCh38: chr19:11021872 T>A

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.(Trp922Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001128849.1:c.2764T>A (p.Trp922Arg) is a missense variant in SMARCA4, a gene in which both loss-of-function and missense variants are established germline disease mechanisms (RTPS2 and Coffin-Siris syndrome, respectively).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.

Multiple lines of computational evidence support a deleterious effect: REVEL score 0.948 and BayesDel score 0.503, meeting PP3 at supporting strength.

The variant is absent from ClinVar and has not been reported in the literature; no prior classification or functional data are available.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	NM_001128849.1:c.2764T>A is a missense variant (p.Trp922Arg). The generic PVS1 framework (PMC6185798) is limited to null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, exon deletions). This missense variant does not fall into any PVS1 null-variant bucket.	pvs1_generic_framework
PS1	Not assessed	No comparator pathogenic variant with the same amino acid change (p.Trp922Arg) has been identified in ClinVar or the literature. The variant is absent from ClinVar entirely.	clinvar
PS2	Not assessed	No de novo occurrence data with confirmed maternity/paternity is available for this variant. No publications mention NM_001128849.1:c.2764T>A.
PS3	Not assessed	No well-established in vitro or in vivo functional studies supporting a damaging effect were identified for this variant. Literature search returned zero PMIDs mentioning NM_001128849.1:c.2764T>A.
PS4	Not assessed	No prevalence data comparing affected individuals versus controls is available for this variant. It is absent from ClinVar and COSMIC.	clinvar
PS5	Not assessed	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no publications reference it.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. Position 922 falls within the helicase ATP-binding domain, but without a VCEP-defined critical domain list or hotspot designation for this residue, PM1 is not met under generic ACMG/AMP criteria.
PM2	Met	NM_001128849.1:c.2764T>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under generic ACMG/AMP criteria, absence from large population cohorts supports pathogenicity at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator pathogenic missense variants identified. PM5 candidate search was unable to confirm eligible same-residue candidates; automatic harvesting skipped.
PM6	Not assessed	No de novo observation (even without paternity/maternity confirmation) has been reported for this variant. Literature search returned zero PMIDs.
PP1	Not assessed	No cosegregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While SMARCA4 missense variants in the helicase domain are associated with Coffin-Siris syndrome, no gene-specific missense constraint metric (Z-score, missense pLI, or regional constraint) was available in the evidence packet to satisfy the low-rate-of-benign-missense requirement under generic ACMG/AMP.
PP3	Met	Multiple lines of in silico computational evidence support a deleterious effect: REVEL score 0.948 (strongly damaging prediction) and BayesDel score 0.503 (damaging prediction, above the 0.27 threshold). SpliceAI predicts no splicing impact (max delta 0.00). The preponderance of computational evidence supports pathogenicity at supporting strength.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for this variant. PP4 requires a phenotype highly specific for a disease with single genetic etiology.
PP5	Not assessed	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no publications mention it.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. An allele frequency >1% required for BA1 is not observed.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. An allele frequency >0.3% required for BS1 is not observed.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No observation data in healthy adults with expected full penetrance at early age is available. The variant is absent from all population databases.
BS3	Not assessed	No well-established in vitro or in vivo functional studies showing no damaging effect are available for this variant. Literature search returned zero PMIDs.
BS4	Not assessed	No segregation data in affected family members is available. Literature search returned zero PMIDs for this variant.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. In SMARCA4, both truncating variants (rhabdoid tumor predisposition syndrome type 2) and missense variants — particularly in the helicase domain (Coffin-Siris syndrome) — are established disease mechanisms. Therefore, BP1 does not apply.
BP2	Not assessed	No data on trans or cis configuration with a pathogenic variant is available for this variant.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion or insertion.
BP4	Not met	Multiple lines of computational evidence suggest a deleterious effect, not a benign one. REVEL score 0.948 (damaging) and BayesDel score 0.503 (damaging) contradict BP4. SpliceAI max delta 0.00 indicates no splicing defect, but the preponderance of in silico evidence points toward pathogenicity.	revel bayesdel spliceai
BP5	Not assessed	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not assessed	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_001128849.1:c.2764T>A is a missense variant (p.Trp922Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
PM3	N/A	SMARCA4-associated conditions are autosomal dominant; PM3 (recessive disorder trans configuration) is not applicable.
PM4	N/A	Variant is a single-nucleotide substitution, not a protein-length-altering in-frame deletion or insertion.

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