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SMARCB1c.787A>GUncertain significance
Print report
Variant interpretation report

SMARCB1 c.787A>G, p.(Ile263Val)

NM_003073.4:c.787A>G NP_003064.2:p.(Ile263Val) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SMARCB1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 5 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent. gnomAD v4.1: AF = 9.29e-06 (15/1
  • 613
  • 888 alleles
  • 0 homozygotes)
  • grpmax FAF = 6.88e-06. gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no splice impact). REVEL: 0.326 (below 0.5). BayesDel: -0.137856 (benign prediction).
Sources
revelbayesdelspliceai ↗

Not met · 5 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.326. BayesDel: -0.137856. SpliceAI max delta: 0.01. All three in silico tools predict no significant deleterious impact.
Sources
revelbayesdelspliceai ↗
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance. No reputable source reports this variant as pathogenic.
Sources
clinvar ↗2539417528492532
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 9.29e-06
  • well below 0.3% BS1 cutoff.
Sources
gnomad_v4 ↗
BP6 No reputable source has classified this variant as benign. ClinVar classification is Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance. No source reports variant as benign.
Sources
clinvar ↗2539417528492532
PS5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance
  • no expert panel or reputable source classifies as pathogenic.
Sources
clinvar ↗2539417528492532

Not assessed · 15 · no assessment recorded

PS1 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. Details ▾Hide ▴
Still missing
  • No comparator variant at codon 263 with different nucleotide change identified in ClinVar or literature.
PS2 No de novo observation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing or parent-of-origin data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence curated.
Still missing
  • No functional assay data (enzymatic activity
  • model organism
  • cell-based assay) available for this variant.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Uncertain significance (2 clinical laboratories)
  • no case counts or phenotype-level data publicly available.
Still missing
  • No case-level phenotype data or case-control comparison for this variant.
Sources
clinvar ↗2539417528492532
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots assessment: residue not significant
  • exact variant not listed.
Still missing
  • No domain-level functional data or ClinGen domain-specific PM1 specification for SMARCB1 available.
PM6 No de novo observation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing or parent-of-origin data available.
PP1 No segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation analysis available.
PP2 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. Details ▾Hide ▴
Still missing
  • No SMARCB1-specific missense constraint data retrieved.
PP4 No patient-specific phenotypic data available for this variant. Details ▾Hide ▴
Still missing
  • No individual-level phenotype information available for carriers of this variant.
BS2 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. Details ▾Hide ▴
Evidence considered
  • 15 heterozygotes in gnomAD v4.1
  • but no individual-level phenotype annotations confirming healthy adult status.
Still missing
  • No confirmed healthy adult carrier data for this variant.
Sources
gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • No functional assay data available
  • in silico predictions alone are insufficient for BS3.
Still missing
  • No dedicated functional studies (enzymatic activity
  • protein interaction
  • model organism) for this variant.
BS4 No family segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation analysis available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • SMARCB1 germline missense variants reported in disease (e.g.
  • p.Lys364Thr in Coffin-Siris syndrome
  • PMID:39563460).
Still missing
  • No gene-specific BP1 specification for SMARCB1 from a VCEP or expert panel.
BP2 No data on observation in trans with a pathogenic variant in SMARCB1. Details ▾Hide ▴
Still missing
  • No phase data or co-occurrence data with other SMARCB1 variants.
BP5 No data on an alternate molecular basis for disease in an individual carrying this variant. Details ▾Hide ▴
Still missing
  • No case report identifying an alternate molecular cause in a carrier of this variant.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Variant class is missense substitution
  • classified as bucket 'other' by generic PVS1 framework (PMC6185798).
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ASkipped per instruction: recessive disorder criteria not applicable for this variant assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per instruction: in-frame indel criteria not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AUnable to confirm classic same-residue PM5 semantics; no comparator candidate variants identified at residue 263 with a different pathogenic missense change. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned no candidates
  • recommendation level is not_applicable.
Sources
pm5_candidates
BA1 N/AThe variant allele frequency in gnomAD v4.1 is 9.29e-06 (0.00093%), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 9.29e-06
  • well below 1% BA1 cutoff.
Sources
gnomad_v4 ↗
BP3 N/ASkipped per instruction: in-frame indel criteria not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.787A>G, p.Ile263Val), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SMARCB1
Transcript
NM_003073.4
Coding (HGVS c.)
NM_003073.4:c.787A>G
Protein (HGVS p.)
NP_003064.2:p.(Ile263Val)
GRCh38
chr22:23816928 A>G
GRCh37
chr22:24159115 A>G
ClinVar
1760986, 1758399

Gene diagram

Every interpreted variant in SMARCB1, mapped onto the exon structure of NM_003073.4. Select a row to find it on the plot.

SMARCB1NM_003073.4
Fetching transcript structure from UCSC…
gnomAD v4.1 15 / 1,613,888 alleles AF 9.29e-06 · 0 homozygotes · FAF 6.88e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 9.3e-06 · 15 / 1,613,888 alleles · 0 hom · FAF 6.9e-06
Remaining individuals1 / 62,506 1.6e-05
European (non-Finnish)14 / 1,179,944 1.2e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -303 bp
0.000
SpliceAI acceptor gainat -128 bp
0.010
SpliceAI donor lossat +435 bp
0.000
SpliceAI donor gainat -364 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.326
BayesDel
-0.138

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no splice impact). REVEL: 0.326 (below 0.5). BayesDel: -0.137856 (benign prediction).
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.326. BayesDel: -0.137856. SpliceAI max delta: 0.01. All three in silico tools predict no significant deleterious impact.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.787A>G, p.Ile263Val), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. Discusses hereditary cancer syndromes at the gene level without mentioning SMARCB1 c.787A>G (p.Ile263Val).
    Does not name this variant
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria (Invitae). Methodological paper describing variant classification framework refinements applied to over 40,000 variants. The specific variant SMARCB1 c.787A>G (p.Ile263Val) is not identified or discussed.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 15 / 1,613,888 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

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

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.