SMARCA4

Final classification

VUS

SMARCA4 c.4927G>T · p.Gly1643Cys

SMARCA4

Gene

SMARCA4

Transcript

NM_001128849.1

HGVS · transcript:coding

NM_001128849.1:c.4927G>T

Consequence

N/A

GRCh38

chr19:11060107 G>T

GRCh37

chr19:11170783 G>T

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

Classification rationale

PM2 BP4 VUS

SMARCA4 c.4927G>T

This variant is extremely rare in population databases, present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, no homozygotes) and absent from gnomAD v2.1, meeting PM2 at supporting strength.¹ Multiple computational predictors suggest no deleterious effect: REVEL score 0.414 (below pathogenic threshold), BayesDel score -0.086 (benign), and SpliceAI predicts no splice impact (max delta 0.0), meeting BP4 at supporting benign strength.² This variant is a missense substitution (p.Gly1643Cys) located in the extreme C-terminal region of SMARCA4, outside the bromodomain (~aa 1488-1590) and helicase domains. PVS1 is not applicable. No functional domain hotspot or established pathogenic comparator at this residue was identified (PM1 and PM5 not met).³ ClinVar classifies this variant as Uncertain significance (1-star, single submitter). No pathogenic or benign assertions from expert panels are available (PP5 and BP6 not met).⁴ Overall, the evidence is limited and conflicting: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not reach the threshold for Likely Pathogenic (≥2 supporting pathogenic), Likely Benign (≥2 supporting benign), or any higher classification tier. The variant is classified as a Variant of Uncertain Significance (VUS).⁵

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 pm5_candidates

4 clinvar ↗

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 · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is extremely rare in population databases: absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, 0 homozygotes), well below the 0.1% PM2 threshold.

gnomAD v2.1: absent. gnomAD v4.1: AF=6.4×10⁻⁷ (1/1551018 alleles

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.414 (below the 0.5 threshold for pathogenicity), BayesDel score -0.086 (benign range), and SpliceAI max delta 0.0 (no predicted splice alteration). Three independent in silico predictors support a neutral or benign effect.

REVEL: 0.414 (indeterminate/benign<0.5). BayesDel: -0.086 (benign). SpliceAI: max delta 0.00 (no splice impact). Three tools concordant for no deleterious effect.

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No evidence of an alternate nucleotide change at codon 1643 resulting in the same amino acid substitution (p.Gly1643Cys) that has been previously established as pathogenic.

PS2 No de novo data available for this variant.

PS3 No functional studies were identified for this variant or a systematically characterized range that includes p.Gly1643.

PS4 The variant has not been observed at significantly increased frequency in affected individuals compared to general population controls.

PM1 The variant lies at p.Gly1643 in the extreme C-terminal region of SMARCA4, outside of characterized functional domains: the bromodomain ends at approximately p.1590 and the helicase domain ends at approximately p.1165.

PM6 No de novo data available for this variant.

PP1 No segregation data available for this variant.

PP2 PP2 requires a gene with a low rate of benign missense variation (typically Z-score >3.09) where missense variants are a common disease mechanism.

PP3 Multiple lines of in silico evidence do not support a deleterious effect.

PP4 No proband phenotype or clinical information is available in the case materials to evaluate whether the patient's phenotype is specific for SMARCA4-related disease.

PP5 PP5 requires a pathogenic assertion from a reputable source (typically ClinVar 3-star expert panel).

Benign

BA1 The variant allele frequency in gnomAD v4.1 is 6.4×10⁻⁷ (0.00006%), far below the 1% BA1 threshold.

BS1 BS1 requires allele frequency greater than expected for the disorder (>0.3% for non-VCEP).

BS2 BS2 requires observation in healthy adults with full penetrance expected at an early age.

BS3 No in vitro or in vivo functional studies demonstrating no deleterious effect of p.Gly1643Cys were identified.

BS4 No segregation data available to assess lack of cosegregation with disease in affected families.

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

BP2 No observation of this variant in trans with a known pathogenic variant in SMARCA4.

BP5 BP5 requires the variant be observed in an affected individual with an alternate molecular basis for disease.

BP6 BP6 requires a benign assertion from a reputable source (typically ClinVar 3-star expert panel).

N/A · 3 PVS1 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.44738e-07; MAF= 0.00006%, 1/1551018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71841e-07; MAF= 0.00009%, 1/1146998 alleles, homozygotes = 0).

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

6.4e-05% · 1 / 1,551,018
0 hom

European (non-Finnish)

1 / 1,146,998

8.7e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3320738)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = -0.0864607.

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

Triaged references · 1 PMID not cited in assessment

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR