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
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-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
PM2 + BP4
→
VUS
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
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
15 / 1,613,888
0.00093%
Highest · Remaining individuals
0.0016%
Homozygotes
0
grpmax FAF
0.00069%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 14 / 1,179,944 | 0.0012% | 0 |
| Admixed American | 0 / 60,028 | — | — |
| European (Finnish) | 0 / 63,810 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,892 | — | — |
| Middle Eastern | 0 / 6,062 | — | — |
| South Asian | 0 / 91,086 | — | — |
| Ashkenazi Jewish | 0 / 29,606 | — | — |
| African/African American | 0 / 75,042 | — | — |
“
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.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1760986)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.326. BayesDel score = -0.137856.
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
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.
Literature · 2 PMIDs triaged · 1 high-priority
2papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25394175 ↗
case observation
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.
The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PP5PS4
Sources & reference links