About SMARCA4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMARCA4 c.4927G>T, p.(Gly1643Cys)
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
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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
This variant is extremely rare in population databases: absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, 0 homozygotes), well below the 0.1% PM2 threshold.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.414 (below the 0.5 threshold for pathogenicity), BayesDel score -0.086 (benign range), and SpliceAI max delta 0.0 (no predicted splice alteration). Three independent in silico predictors support a neutral or benign 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,551,018 alleles
gnomAD v4.1: 1 / 1,551,018 alleles. Recorded AF 6.44738e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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: 2 met · 15 not met · 6 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is extremely rare in population databases, present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, no homozygotes) and absent from gnomAD v2.1, meeting PM2 at supporting strength.
Multiple computational predictors suggest no deleterious effect: REVEL score 0.414 (below pathogenic threshold), BayesDel score -0.086 (benign), and SpliceAI predicts no splice impact (max delta 0.0), meeting BP4 at supporting benign strength.
This variant is a missense substitution (p.Gly1643Cys) located in the extreme C-terminal region of SMARCA4, outside the bromodomain (~aa 1488-1590) and helicase domains. PVS1 is not applicable. No functional domain hotspot or established pathogenic comparator at this residue was identified (PM1 and PM5 not met).
ClinVar classifies this variant as Uncertain significance (1-star, single submitter). No pathogenic or benign assertions from expert panels are available (PP5 and BP6 not met).
Overall, the evidence is limited and conflicting: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not reach the threshold for Likely Pathogenic (≥2 supporting pathogenic), Likely Benign (≥2 supporting benign), or any higher classification tier. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases: absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, 0 homozygotes), well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: AF=6.4×10⁻⁷ (1/1
- 551
- 018 alleles
- 0 homozygotes). gnomAD-Canada v1.0: absent.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: REVEL score 0.414 (below the 0.5 threshold for pathogenicity), BayesDel score -0.086 (benign range), and SpliceAI max delta 0.0 (no predicted splice alteration). Three independent in silico predictors support a neutral or benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (indeterminate/benign
- <0.5). BayesDel: -0.086 (benign). SpliceAI: max delta 0.00 (no splice impact). Three tools concordant for no deleterious effect.
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No evidence of an alternate nucleotide change at codon 1643 resulting in the same amino acid substitution (p.Gly1643Cys) that has been previously established as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide variants at codon 1643 with established pathogenicity were identified in ClinVar or literature.
Still missing
- No same-amino-acid comparator variants identified at codon 1643.
PS4 The variant has not been observed at significantly increased frequency in affected individuals compared to general population controls. A single ClinVar submission from Ambry Genetics classifies it as VUS with no detailed case-level phenotypic information provided. Details ▾Hide ▴
Evidence considered
- ClinVar variation 3320738: Uncertain significance
- single submitter (Ambry Genetics)
- no detailed case counts or phenotypic enrichment data.
Still missing
- No case-control studies or cohort-level prevalence data available.
Sources
PM1 The variant lies at p.Gly1643 in the extreme C-terminal region of SMARCA4, outside of characterized functional domains: the bromodomain ends at approximately p.1590 and the helicase domain ends at approximately p.1165. Cancerhotspots.org does not identify this residue as a statistically significant hotspot, and no literature identifies a well-characterized critical functional domain spanning this position. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed. Position 1643 is C-terminal to the bromodomain (~aa 1488-1590) and helicase domains.
Still missing
- No functional domain characterization literature specifically covering the extreme C-terminal region around aa 1643.
PP2 PP2 requires a gene with a low rate of benign missense variation (typically Z-score >3.09) where missense variants are a common disease mechanism. SMARCA4 missense variants cause Coffin-Siris syndrome, but gene-level constraint data (HCI Prior) is not available for SMARCA4. Without evidence of a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI Prior not available for SMARCA4. SMARCA4 has both missense (CSS) and truncating (RTPS2) disease mechanisms.
Still missing
- No gene-level missense constraint data (Z-score
- HCI Prior) available for SMARCA4.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.414 (below the 0.5 threshold for pathogenic prediction), BayesDel score is -0.086 (benign range), and SpliceAI predicts no splice impact (max delta = 0.0). The majority of available computational tools suggest a neutral or non-deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (<0.5
- not deleterious). BayesDel: -0.086 (benign). SpliceAI: max delta 0.00 (no splice impact).
Sources
PP5 PP5 requires a pathogenic assertion from a reputable source (typically ClinVar 3-star expert panel). This variant is classified as Uncertain significance in ClinVar with 1-star review status (criteria provided, single submitter by Ambry Genetics). The automatic PP5 supporting rule for 3-star expert panel submissions does not apply at this review tier. Details ▾Hide ▴
Evidence considered
- ClinVar variation 3320738: Uncertain significance
- single submitter (1-star)
- not an expert panel submission.
Sources
BA1 The variant allele frequency in gnomAD v4.1 is 6.4×10⁻⁷ (0.00006%), far below the 1% BA1 threshold. BA1 requires AF >1% in any population. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max population AF: 8.7×10⁻⁷ (European non-Finnish). Far below BA1 1% threshold.
Sources
BS1 BS1 requires allele frequency greater than expected for the disorder (>0.3% for non-VCEP). The variant AF is 6.4×10⁻⁷, well below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=6.4×10⁻⁷ (0.00006%)
- far below 0.3% BS1 threshold.
Sources
BS2 BS2 requires observation in healthy adults with full penetrance expected at an early age. Only 1 heterozygous individual identified in gnomAD v4.1 out of 1.55M alleles; no homozygous observations. This is insufficient to establish the variant as benign in healthy controls. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 heterozygous carrier
- 0 homozygotes
- AF=6.4×10⁻⁷. Single observation insufficient for BS2.
Sources
BS3 No in vitro or in vivo functional studies demonstrating no deleterious effect of p.Gly1643Cys were identified. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific benign functional data.
Still missing
- No functional studies demonstrating neutral effect of p.Gly1643Cys.
Sources
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. SMARCA4 has a dual disease mechanism: truncating variants cause rhabdoid tumor predisposition syndrome type 2 (RTPS2) via loss of function, while missense variants (particularly in the helicase domain) cause Coffin-Siris syndrome via dominant-negative or gain-of-function effects. Since missense variants are a recognized disease mechanism in SMARCA4, BP1 does not apply. Details ▾Hide ▴
Evidence considered
- SMARCA4 genotype-phenotype correlation: missense variants cause Coffin-Siris syndrome (CSS)
- truncating variants cause RTPS2. Missense is a known disease mechanism.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic variant in SMARCA4. BP2 applies to recessive disorders; SMARCA4-related conditions are autosomal dominant. Details ▾Hide ▴
Evidence considered
- No trans-phase observation data available. SMARCA4 disease is autosomal dominant.
BP5 BP5 requires the variant be observed in an affected individual with an alternate molecular basis for disease. No such observation is available for this variant. The sole ClinVar submission does not report an alternate molecular diagnosis. Details ▾Hide ▴
Evidence considered
- No evidence of this variant co-occurring with an alternate causal molecular finding in an affected individual.
Still missing
- No case data with alternate molecular diagnosis available.
BP6 BP6 requires a benign assertion from a reputable source (typically ClinVar 3-star expert panel). This variant is classified as Uncertain significance with 1-star review status; it is not asserted as Benign or Likely Benign by any submitter. Details ▾Hide ▴
Evidence considered
- ClinVar variation 3320738: Uncertain significance
- 1-star review
- no benign assertion from any submitter.
Sources
PS5 No previously established pathogenic variant at codon 1643 with a different amino acid change was identified to satisfy the PS5 requirement for same-residue alternate pathogenic change. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator variants at p.Gly1643 were identified in ClinVar or PM5 candidate search.
Still missing
- No established pathogenic variants at the same codon with a different amino acid change.
Not assessed · 6 · no assessment recorded
PS2 No de novo data available for this variant. Parental testing results are not present in the case materials or literature. Details ▾Hide ▴
Still missing
- No parental testing or de novo confirmation available.
PS3 No functional studies were identified for this variant or a systematically characterized range that includes p.Gly1643. OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data curated.
Still missing
- No functional characterization of p.Gly1643Cys or a systematically assayed range including this residue.
Sources
PM6 No de novo data available for this variant. No report of confirmed de novo occurrence in any source. Details ▾Hide ▴
Still missing
- No de novo confirmation or parental testing data available.
PP1 No segregation data available for this variant. No family studies or cosegregation analysis present in the case materials. Details ▾Hide ▴
Still missing
- No segregation or family studies available.
PP4 No proband phenotype or clinical information is available in the case materials to evaluate whether the patient's phenotype is specific for SMARCA4-related disease. Details ▾Hide ▴
Still missing
- No proband clinical phenotype available for specificity assessment.
BS4 No segregation data available to assess lack of cosegregation with disease in affected families. Details ▾Hide ▴
Still missing
- No family segregation data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: this is a missense variant (p.Gly1643Cys) and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Generic PVS1 framework assessment was not triggered. Details ▾Hide ▴
Evidence considered
- Missense variant classified as variant_bucket='other' by PVS1 framework
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/APM5 candidate search was unable to confirm classic same-residue PM5 semantics; no same-residue comparator variants with pathogenic classifications were identified at p.Gly1643 in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate module: eligible_for_classic_pm5_search=false
- 0 same-residue candidates
- recommendation level=not_applicable.
Sources
pm5_candidates
BP7 N/ABP7 applies only to synonymous (silent) variants. This is a missense variant (c.4927G>T, p.Gly1643Cys), so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 does not apply.
Identifiers
- Gene
- SMARCA4
- Transcript
- NM_001128849.1
- Coding (HGVS c.)
- NM_001128849.1:c.4927G>T
- Protein (HGVS p.)
- NP_001122321.1:p.(Gly1643Cys)
- GRCh38
- chr19:11060107 G>T
- GRCh37
- chr19:11170783 G>T
- ClinVar
- 3320738
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
1 / 1,551,018 alleles
AF 6.45e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.4e-07 · 1 / 1,551,018 alleles · 0 hom
| European (non-Finnish)1 / 1,146,998 | 8.7e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.44738e-07; MAF= 0.00006%, 1/1551018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71841e-07; MAF= 0.00009%, 1/1146998 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.414
- BayesDel
- -0.086
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: REVEL score 0.414 (below the 0.5 threshold for pathogenicity), BayesDel score -0.086 (benign range), and SpliceAI max delta 0.0 (no predicted splice alteration). Three independent in silico predictors support a neutral or benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (indeterminate/benign
- <0.5). BayesDel: -0.086 (benign). SpliceAI: max delta 0.00 (no splice impact). Three tools concordant for no deleterious effect.
Sources
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.414 (below the 0.5 threshold for pathogenic prediction), BayesDel score is -0.086 (benign range), and SpliceAI predicts no splice impact (max delta = 0.0). The majority of available computational tools suggest a neutral or non-deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (<0.5
- not deleterious). BayesDel: -0.086 (benign). SpliceAI: max delta 0.00 (no splice impact).
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants. This is a missense variant (c.4927G>T, p.Gly1643Cys), so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = -0.0864607.
1 paper record 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
-
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. · 2015This is an ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. It does not discuss SMARCA4 or the specific variant NM_001128849.1:c.4927G>T.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,551,018 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3320738/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-11170783-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-11060107-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-11060107-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001128849.1%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/SMARCA4/G1643C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SMARCA4+c.4927G%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= 6.44738e-07; MAF= 0.00006%, 1/1551018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71841e-07; MAF= 0.00009%, 1/1146998 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3320738)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = -0.0864607.
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.