NM_003073.4:c.787A>G

SMARCB1 · NP_003064.2:p.(Ile263Val) · NM_003073.4

GRCh37: chr22:24159115 A>G · GRCh38: chr22:23816928 A>G

Gene: SMARCB1 Transcript: NM_003073.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

SMARCB1

Transcript

NM_003073.4

Protein

NP_003064.2:p.(Ile263Val)

gnomAD AF

9.294325256771226e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories.

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.

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_003073.4:c.787A>G is a missense variant (p.Ile263Val) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No evidence of a different nucleotide change at codon 263 producing the same amino acid substitution (p.Ile263Val) that has been previously classified as pathogenic.
PS2	Not assessed	No de novo observation data available for this variant.
PS3	Not assessed	No variant-specific functional studies identified. OncoKB did not identify variant-specific reviewed functional evidence. In silico predictions alone do not constitute functional assay evidence for PS3.	oncokb
PS4	Not assessed	No case-control data or variant-specific case counts available. The two ClinVar submissions are from clinical testing laboratories without publicly available case-level phenotype data. The cited PMIDs (25394175, 28492532) are methodological/guideline papers, not case reports for this variant.	clinvar
PS5	Not met	No reputable source has classified this variant as pathogenic. ClinVar classification is Uncertain significance from two clinical laboratories. The two associated PMIDs do not classify this variant as pathogenic.	clinvar
PM1	Not assessed	The variant does not lie in a statistically significant hotspot per the Cancer Hotspots assessment. No domain-specific functional data was recovered for residue 263 to establish a critical functional domain.
PM2	Met	The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (allele frequency = 9.29e-06, 15/1,613,888 alleles, 0 homozygotes; grpmax FAF = 6.88e-06). This is well below the 0.1% PM2 threshold for generic ACMG/AMP. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no comparator candidate variants identified at residue 263 with a different pathogenic missense change.	pm5_candidates
PM6	Not assessed	No de novo observation data available for this variant.
PP1	Not assessed	No segregation data available for this variant.
PP2	Not assessed	No gene-level constraint metrics (e.g., Missense Z-score, gnomAD constraint) were retrieved to establish a low rate of benign missense variation in SMARCB1.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.326 is below the typical pathogenic threshold of 0.5. BayesDel score -0.137856 is negative, predicting a benign effect. SpliceAI max delta score 0.01 predicts no splicing impact.	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotypic data available for this variant.
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar classification is Uncertain significance. The two associated PMIDs (25394175 and 28492532) are methodological papers that do not specifically address or classify this variant.	clinvar
BA1	N/A	The variant allele frequency in gnomAD v4.1 is 9.29e-06 (0.00093%), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 0.00093% (9.29e-06), far below the 0.3% BS1 threshold for generic ACMG/AMP.	gnomad_v4
BS2	Not assessed	While the variant is observed in gnomAD v4.1 in 15 heterozygous individuals, gnomAD does not provide individual-level phenotype confirmation of healthy adult status. For a disorder with variable expressivity and age-dependent penetrance, observation at very low frequency in a population database does not independently satisfy BS2 without confirmed asymptomatic carrier data.	gnomad_v4
BS3	Not assessed	No variant-specific functional assays demonstrating no damaging effect are available. In silico scores (REVEL 0.326, BayesDel -0.137856) are suggestive but do not constitute functional assay evidence for BS3.
BS4	Not assessed	No family segregation data available for this variant.
BP1	Not assessed	While loss-of-function is an established disease mechanism for SMARCB1, missense variants are also documented as disease-causing in SMARCB1-related disorders (e.g., Coffin-Siris syndrome, schwannomatosis). The gene is not limited to a truncating-only disease mechanism, and BP1 cannot be applied without confirming that this specific missense change is not in a domain where missense variants are pathogenic.
BP2	Not assessed	No data on observation in trans with a pathogenic variant in SMARCB1.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI max delta score is 0.01 (no predicted splicing impact). REVEL score is 0.326 (below pathogenic threshold of 0.5). BayesDel score is -0.137856 (negative, predicting a benign effect). Three independent in silico predictors concur on no deleterious effect.	revel bayesdel spliceai
BP5	Not assessed	No data on an alternate molecular basis for disease in an individual carrying this variant.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar classification is Uncertain significance.	clinvar
BP7	N/A	This is a missense variant (c.787A>G, p.Ile263Val), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Skipped per instruction: in-frame indel criteria not applicable to a substitution variant.
PM3	N/A	Skipped per instruction: recessive disorder criteria not applicable for this variant assessment.
PM4	N/A	Skipped per instruction: in-frame indel criteria not applicable to a substitution variant.

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