About SMARCA4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMARCA4 c.335C>T, p.(Pro112Leu)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is present at extremely low frequency in population databases. gnomAD v2.1 AF=3.19e-05 (0.00319%, 1/31,372 alleles), gnomAD v4.1 AF=1.86e-06 (0.00019%, 3/1,613,788 alleles), both far below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation frequency is African/African American at 0.0115% (v2.1) and 0.0040% (v4.1).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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 moderate; combination = 1 moderate, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,613,788 alleles
gnomAD v4.1: 3 / 1,613,788 alleles. Recorded AF 1.85898e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18756e-05; MAF= 0.00319%, 1/31372 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions
3 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
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. SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOH
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 13 not met · 10 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001128849.1:c.335C>T (p.Pro112Leu) is a missense variant in SMARCA4 identified in the germline context.
This variant is present at extremely low frequency in population databases (gnomAD v2.1: 1/31,372 alleles, 0.003%; gnomAD v4.1: 3/1,613,788 alleles, 0.0002%), meeting PM2 at moderate strength.
No functional studies, case-control data, segregation data, or de novo observations are available for this variant. In silico tools produce conflicting predictions (REVEL 0.609 pathogenic; BayesDel -0.0146 benign). ClinVar classification is Uncertain significance with single-submitter review status.
Only one moderate criterion (PM2) is met. Under generic ACMG/AMP 2015 combination rules, a single moderate criterion is insufficient to reach Likely pathogenic or Likely benign. The variant is classified as Uncertain significance.
No criteria match.
Met · 1
PM2 ModerateThis variant is present at extremely low frequency in population databases. gnomAD v2.1 AF=3.19e-05 (0.00319%, 1/31,372 alleles), gnomAD v4.1 AF=1.86e-06 (0.00019%, 3/1,613,788 alleles), both far below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation frequency is African/African American at 0.0115% (v2.1) and 0.0040% (v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/31
- 372 alleles (0.0032%)
- genome only
- gnomAD v4.1: 3/1
- 613
- 788 alleles (0.00019%)
- joint exome+genome
- grpmax FAF=1.06e-05
- gnomAD-Canada: absent
- All frequencies well below PM2 threshold of 0.1%
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No evidence that the same amino acid change (p.Pro112Leu) has been established as pathogenic via a different nucleotide change. No literature or database record identifies a pathogenic PS1-equivalent variant at this residue. Details ▾Hide ▴
Evidence considered
- ClinVar variation 389324: only this variant reported at Pro112
- no alternative nucleotide changes producing p.Pro112Leu identified
- PM5 candidate search returned no same-residue comparator variants
Sources
clinvar ↗pm5_candidates
PS3 No functional studies identified for NM_001128849.1:c.335C>T (p.Pro112Leu). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publications with experimental functional data for this exact variant or a systematically characterized range including position 112 were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific reviewed functional evidence
- Literature triage: 4 PMIDs identified
- none contain variant-specific functional data
- No COSMIC somatic observations to suggest functional relevance
Still missing
- No functional studies available for this variant
- experimental characterization of p.Pro112Leu would be needed to assess PS3
Sources
PM1 Position 112 in SMARCA4 lies in the N-terminal region outside characterized critical functional domains (QLQ, HSA, BRK, DExx helicase, HELICc, Bromodomain). Cancerhotspots.org does not identify this as a statistically significant residue. No mutational hotspot or critical functional domain evidence supports PM1. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed
- Position 112 is N-terminal to established SMARCA4 functional domains
Sources
PM5 No same-residue pathogenic missense comparator variants identified at Pro112. Automated PM5 candidate harvesting returned no candidates; same-residue ClinVar search found no pathogenic missense at this position. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 candidates
- eligible_for_classic_pm5_search=false
- No different missense change at Pro112 identified in ClinVar as pathogenic
Sources
pm5_candidates
PP3 In silico tools produce conflicting predictions. REVEL score 0.609 suggests a deleterious effect, but BayesDel score -0.0146 is in the benign range. Multiple lines of computational evidence do not agree on a deleterious effect; PP3 requires concordant pathogenic predictions from multiple tools. Details ▾Hide ▴
Evidence considered
- REVEL: 0.609 (pathogenic-leaning
- above 0.5 threshold)
- BayesDel: -0.0146 (benign-leaning
- negative score)
- Tools conflict
- no consensus deleterious prediction across multiple algorithms
Sources
revelbayesdel
PP5 ClinVar classification for this variant is Uncertain significance (3 clinical laboratories) and Likely benign (1 laboratory), all with criteria provided, single submitter review status. No expert panel (3-star) classification as pathogenic. PP5 requires reputable source classification as pathogenic; VUS does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar variation 389324: VUS with 3 clinical labs
- Likely benign with 1 lab
- Review status: criteria provided
- single submitter (1-star)
- No expert panel review (not 3-star)
- PP5 not applicable
Sources
BA1 gnomAD allele frequency far below BA1 threshold of 1%. Highest observed AF is 0.0115% in African/African American (v2.1) and 0.0040% in African/African American (v4.1). This is not a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF: 0.0115% (AFR)
- gnomAD v4.1 max AF: 0.0040% (AFR)
- Both far below BA1 threshold of 1%
Sources
BS1 gnomAD allele frequency far below BS1 threshold of 0.3%. Highest observed AF is 0.0115% in African/African American (v2.1). Population frequency is not elevated above the benign threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF: 0.0115% (AFR)
- gnomAD v4.1 max AF: 0.0040% (AFR)
- Both far below BS1 threshold of 0.3%
Sources
BS2 Only 4 total allele observations across gnomAD v2+v4 combined (>1.6M alleles). For an autosomal dominant tumor predisposition syndrome (RTPS2) with onset often in infancy/childhood, observation in 3-4 individuals in population databases is insufficient to meet BS2, which requires observation in multiple healthy adults at an age when disease would be expected to manifest with full penetrance. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1 allele (genome only
- AFR)
- gnomAD v4.1: 3 alleles (all AFR)
- Total: 4 observations
- insufficient for BS2 in an early-onset dominant disorder
Sources
BP1 SMARCA4 missense variants are an established disease mechanism. Heterozygous missense variants in SMARCA4 cause Coffin-Siris syndrome, while truncating variants cause RTPS2. BP1 applies only to genes where primarily truncating variants cause disease; SMARCA4 has both missense and truncating as distinct disease mechanisms, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- SMARCA4 missense variants cause Coffin-Siris syndrome (CSS)
- SMARCA4 truncating variants cause Rhabdoid Tumor Predisposition Syndrome type 2 (RTPS2)
- Gene has established disease mechanisms for both variant types
- BP1 not applicable
Sources
PMID:25741868 ↗pvs1_gene_context
BP4 In silico tools produce conflicting predictions. REVEL score 0.609 suggests a deleterious effect. Only BayesDel (-0.0146) predicts benign. Multiple lines of computational evidence do not agree on a benign effect; BP4 requires multiple tools to predict no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.609 (pathogenic-leaning)
- BayesDel: -0.0146 (benign-leaning)
- Tools conflict
- no consensus benign prediction
Sources
revelbayesdel
BP6 ClinVar classification for this variant is Uncertain significance (3 labs) and Likely benign (1 lab), all with single-submitter review status. No expert panel classification as benign. BP6 requires a reputable source to classify as benign; VUS does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar variation 389324: VUS (3 labs)
- Likely benign (1 lab)
- No expert panel review
- no 3-star benign classification
Sources
PS5 No different pathogenic missense change has been identified at the same residue (Pro112). PM5 candidate search returned no comparator variants. No literature evidence of a pathogenic missense at codon 112. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
- eligible_for_classic_pm5_search=false
- ClinVar: no other pathogenic missense variants at Pro112
Sources
pm5_candidatesclinvar ↗
Not assessed · 10 · no assessment recorded
PS2 No de novo data available. No publications report this variant as a confirmed de novo occurrence. Details ▾Hide ▴
Still missing
- No de novo testing data or family studies available for this variant
PS4 No case-control studies or variant-specific case prevalence data available. ClinVar submissions (4 total, all single-submitter) do not provide detailed case-level phenotype information to support PS4. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 submissions (3 VUS
- 1 Likely benign)
- all single-submitter clinical testing
- no case-level detail
Still missing
- No case-control comparison data
- no variant-specific case reports with clinical detail
Sources
PM6 No de novo data available. PM6 requires a confirmed de novo observation with confirmed maternity/paternity. Details ▾Hide ▴
Still missing
- No de novo testing data available for this variant
PP1 No segregation data available. No family studies or cosegregation analysis reported for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
PP2 Insufficient constraint data to apply PP2. While SMARCA4 missense variants are an established disease mechanism (Coffin-Siris syndrome), explicit gene-level missense constraint metrics (Z-score) were not available in the evidence brief. Cannot reliably determine whether the gene has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- SMARCA4 is known to have missense variants as a disease mechanism (Coffin-Siris syndrome)
Still missing
- Missense constraint Z-score or gnomAD missense oe ratio needed to assess PP2
PP4 Patient phenotype information not available. Cannot assess whether the patient's phenotype is highly specific for SMARCA4-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data provided
BS3 No functional studies available showing that this variant has no deleterious effect. BS3 requires experimental evidence demonstrating normal protein function. Details ▾Hide ▴
Still missing
- No functional studies available to assess normal vs. deleterious effect
BS4 No segregation data available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No data available on observation of this variant in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No phase data or trans observation data available
BP5 No data available on an alternate molecular basis for disease in this individual. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data available
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (NM_001128849.1:c.335C>T, p.Pro112Leu); does not fall into null-variant categories (nonsense, frameshift, or canonical splice ±1,2). PVS1 decision framework not applied. Details ▾Hide ▴
Evidence considered
- Variant classified as missense substitution by Mutalyzer normalization
- pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 applies to synonymous (silent) variants where splicing is predicted to be unaffected. NM_001128849.1:c.335C>T is a missense variant (p.Pro112Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Variant type: missense substitution
- not synonymous
Identifiers
- Gene
- SMARCA4
- Transcript
- NM_001128849.1
- Coding (HGVS c.)
- NM_001128849.1:c.335C>T
- Protein (HGVS p.)
- NP_001122321.1:p.(Pro112Leu)
- GRCh38
- chr19:10985385 C>T
- GRCh37
- chr19:11096061 C>T
- ClinVar
- 389324
Gene diagram
Every interpreted variant in SMARCA4, mapped onto the exon structure of NM_001128849.1. Select a row to find it on the plot.
SMARCA4NM_001128849.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SMARCA4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3 / 1,613,788 alleles
AF 1.86e-06 · 0 homozygotes · FAF 1.06e-05
gnomAD v2.1
1 / 31,372 alleles
AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,613,788 alleles · 0 hom · FAF 1.1e-05
| African/African American3 / 74,916 | 4e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 3.2e-05 · 1 / 31,372 alleles · 0 hom
| African/African American1 / 8,708 | 0.00011 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85898e-06; MAF= 0.00019%, 3/1613788 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00449e-05; MAF= 0.00400%, 3/74916 alleles, homozygotes = 0); grpmax FAF= 1.063e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18756e-05; MAF= 0.00319%, 1/31372 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.609
- BayesDel
- -0.015
How the predictions were used
PP3 In silico tools produce conflicting predictions. REVEL score 0.609 suggests a deleterious effect, but BayesDel score -0.0146 is in the benign range. Multiple lines of computational evidence do not agree on a deleterious effect; PP3 requires concordant pathogenic predictions from multiple tools. Details ▾Hide ▴
Evidence considered
- REVEL: 0.609 (pathogenic-leaning
- above 0.5 threshold)
- BayesDel: -0.0146 (benign-leaning
- negative score)
- Tools conflict
- no consensus deleterious prediction across multiple algorithms
Sources
revelbayesdel
BP4 In silico tools produce conflicting predictions. REVEL score 0.609 suggests a deleterious effect. Only BayesDel (-0.0146) predicts benign. Multiple lines of computational evidence do not agree on a benign effect; BP4 requires multiple tools to predict no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.609 (pathogenic-leaning)
- BayesDel: -0.0146 (benign-leaning)
- Tools conflict
- no consensus benign prediction
Sources
revelbayesdel
BP7 N/ABP7 applies to synonymous (silent) variants where splicing is predicted to be unaffected. NM_001128849.1:c.335C>T is a missense variant (p.Pro112Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Variant type: missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.609. BayesDel score = -0.0146094.
3 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
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP 2015 standards and guidelines for interpretation of sequence variants. Provides the generic classification framework and combination rules. NM_001128849.1:c.335C>T was not identified in this paper.Does not name this variant
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PMID 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.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Provides general guidance for hereditary cancer referral. NM_001128849.1:c.335C>T was not identified in this paper.Does not name this variant
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PMID 29215836 ↗Rhabdoid Tumor Predisposition Syndrome.Adam MP et al. · 1993GeneReviews entry on Rhabdoid Tumor Predisposition Syndrome. Provides gene-level overview of SMARCA4 in RTPS2. NM_001128849.1:c.335C>T was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,613,788 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
3 Uncertain significance · 1 Likely benign
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/389324/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-11096061-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-10985385-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-10985385-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001128849.1%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/SMARCA4/P112L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SMARCA4+c.335C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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= 1.85898e-06; MAF= 0.00019%, 3/1613788 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00449e-05; MAF= 0.00400%, 3/74916 alleles, homozygotes = 0); grpmax FAF= 1.063e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18756e-05; MAF= 0.00319%, 1/31372 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 389324)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.609. BayesDel score = -0.0146094.
Functional
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
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.