Classification rationale

PM2PP3 VUS

SMARCA4 c.2764T>A

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.¹ Multiple lines of computational evidence support a deleterious effect: REVEL score 0.948 and BayesDel score 0.503, meeting PP3 at supporting strength.² The variant is absent from ClinVar and has not been reported in the literature; no prior classification or functional data are available.³

PM2 + PP3 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdel

3 clinvar ↗

Gene diagram · NM_001128849.1 · variants mapped to exon structure

SMARCA4 NM_001128849.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (genomes).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

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 score 0.948 (damagingthreshold >0.75).BayesDel score 0.503 (damaging

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No comparator pathogenic variant with the same amino acid change (p.Trp922Arg) has been identified in ClinVar or the literature.

PS2 No de novo occurrence data with confirmed maternity/paternity is available for this variant.

PS3 No well-established in vitro or in vivo functional studies supporting a damaging effect were identified for this variant.

PS4 No prevalence data comparing affected individuals versus controls is available for this variant.

PM1 This variant does not lie in a statistically significant mutational hotspot.

PM6 No de novo observation (even without paternity/maternity confirmation) has been reported for this variant.

PP1 No cosegregation data with disease in multiple affected family members is available for this variant.

PP2 PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism.

PP4 No patient phenotype or family history data are available for this variant.

PP5 No reputable source has reported this variant as pathogenic.

Benign

BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS2 No observation data in healthy adults with expected full penetrance at early age is available.

BS3 No well-established in vitro or in vivo functional studies showing no damaging effect are available for this variant.

BS4 No segregation data in affected family members is available.

BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease.

BP2 No data on trans or cis configuration with a pathogenic variant is available for this variant.

BP4 Multiple lines of computational evidence suggest a deleterious effect, not a benign one.

BP5 No observation of this variant in a case with an alternate molecular basis for disease is available.

BP6 No reputable source has reported this variant as benign.

N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7

Research & evidence

Population frequency

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.948. BayesDel score = 0.502973.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOH

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots