Starting

Initialising…

SMARCB1

Final classification

VUS

SMARCB1 c.787A>G · p.Ile263Val

SMARCB1

NM_003073.4:c.787A>G (p.Ile263Val) is a missense variant in exon 6 of SMARCB1.

Gene

SMARCB1

Transcript

NM_003073.4

HGVS · transcript:coding

NM_003073.4:c.787A>G

Consequence

N/A

GRCh38

chr22:23816928 A>G

GRCh37

chr22:24159115 A>G

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

SMARCB1 c.787A>G

NM_003073.4:c.787A>G (p.Ile263Val) is a missense variant in exon 6 of SMARCB1. The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (9.29e-06, 15 heterozygotes, 0 homozygotes), meeting PM2 at supporting level.¹ Multiple in silico predictors suggest no significant impact: SpliceAI max delta 0.01, REVEL 0.326, BayesDel -0.137856, meeting BP4 at supporting_benign level.² This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories.³ No functional studies, segregation data, de novo observations, or case-control data are available for this variant. With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to reach a likely pathogenic or likely benign classification.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_003073.4 · variants mapped to exon structure

SMARCB1 NM_003073.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.29433e-06; MAF= 0.00093%, 15/1613888 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0); grpmax FAF= 6.88e-06.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00093% · 15 / 1,613,888
0 hom · FAF 0.00069%

Remaining individuals 1 / 62,506	0.0016%
European (non-Finnish) 14 / 1,179,944	0.0012%

+ 8 not observed (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 (2 clinical laboratories). (ClinVarID = 1760986)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.326. BayesDel score = -0.137856.

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. SMARCB1, a protein involved in chromatin remodeling, is inactivated by mutation or deletion in various cancer types including soft tissue sarcomas and

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs 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

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR