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SMARCA4c.2764T>AUncertain significance
Print report
Variant interpretation report

SMARCA4 c.2764T>A, p.(Trp922Arg)

NM_001128849.1:c.2764T>A NP_001122321.1:p.(Trp922Arg) 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 SMARCA4

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

NM_001128849.1:c.2764T>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under generic ACMG/AMP criteria, absence from large population cohorts supports pathogenicity at supporting strength.

PP3Supporting
PP3 · supporting

Multiple lines of in silico computational evidence support a deleterious effect: REVEL score 0.948 (strongly damaging prediction) and BayesDel score 0.503 (damaging prediction, above the 0.27 threshold). SpliceAI predicts no splicing impact (max delta 0.00). The preponderance of computational evidence supports pathogenicity at supporting strength.

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 supporting, PP3 supporting; combination = 2 supporting, 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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
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 · 6 not met · 15 not assessed · 6 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_001128849.1:c.2764T>A (p.Trp922Arg) is a missense variant in SMARCA4, a gene in which both loss-of-function and missense variants are established germline disease mechanisms (RTPS2 and Coffin-Siris syndrome, respectively).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.

Multiple lines of computational evidence support a deleterious effect: REVEL score 0.948 and BayesDel score 0.503, meeting PP3 at supporting strength.

The variant is absent from ClinVar and has not been reported in the literature; no prior classification or functional data are available.

Met · 2

PM2 SupportingNM_001128849.1:c.2764T>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under generic ACMG/AMP criteria, absence from large population cohorts supports pathogenicity at supporting strength. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple lines of in silico computational evidence support a deleterious effect: REVEL score 0.948 (strongly damaging prediction) and BayesDel score 0.503 (damaging prediction, above the 0.27 threshold). SpliceAI predicts no splicing impact (max delta 0.00). The preponderance of computational evidence supports pathogenicity at supporting strength. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.948 (damaging
  • threshold >0.75).
  • BayesDel score 0.503 (damaging
  • threshold >0.27).
  • SpliceAI max delta 0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant mutational hotspot. Position 922 falls within the helicase ATP-binding domain, but without a VCEP-defined critical domain list or hotspot designation for this residue, PM1 is not met under generic ACMG/AMP criteria. Details ▾Hide ▴
Evidence considered
  • Position 922 not in a statistically significant hotspot per cancerhotspots.org.
Still missing
  • No VCEP-defined critical domain boundaries for SMARCA4. The helicase domain is functionally important but formal PM1 requires hotspot or consensus critical domain designation.
PP2 PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While SMARCA4 missense variants in the helicase domain are associated with Coffin-Siris syndrome, no gene-specific missense constraint metric (Z-score, missense pLI, or regional constraint) was available in the evidence packet to satisfy the low-rate-of-benign-missense requirement under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
  • SMARCA4 missense variants are a known disease mechanism (Coffin-Siris syndrome)
  • but no constraint metric confirming low benign missense rate was available.
Still missing
  • Gene-level missense constraint metric (e.g.
  • gnomAD missense Z-score) not available for automated PP2 adjudication.
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. An allele frequency >1% required for BA1 is not observed. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.00 across all gnomAD datasets
  • does not meet BA1 threshold (>1%).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. An allele frequency >0.3% required for BS1 is not observed. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.00 across all gnomAD datasets
  • does not meet BS1 threshold (>0.3%).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. In SMARCA4, both truncating variants (rhabdoid tumor predisposition syndrome type 2) and missense variants — particularly in the helicase domain (Coffin-Siris syndrome) — are established disease mechanisms. Therefore, BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • SMARCA4 missense variants in the helicase domain are a recognized cause of Coffin-Siris syndrome
  • missense is an established disease mechanism alongside truncating variants.
BP4 Multiple lines of computational evidence suggest a deleterious effect, not a benign one. REVEL score 0.948 (damaging) and BayesDel score 0.503 (damaging) contradict BP4. SpliceAI max delta 0.00 indicates no splicing defect, but the preponderance of in silico evidence points toward pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.948 (damaging) opposes benign prediction.
  • BayesDel 0.503 (damaging) opposes benign prediction.
Sources
revelbayesdelspliceai ↗

Not assessed · 15 · no assessment recorded

PS1 No comparator pathogenic variant with the same amino acid change (p.Trp922Arg) has been identified in ClinVar or the literature. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid comparator available for PS1 evaluation.
Still missing
  • No prior p.Trp922Arg classification in any database.
Sources
clinvar ↗
PS2 No de novo occurrence data with confirmed maternity/paternity is available for this variant. No publications mention NM_001128849.1:c.2764T>A. Details ▾Hide ▴
Still missing
  • No de novo data available from publications or clinical records.
PS3 No well-established in vitro or in vivo functional studies supporting a damaging effect were identified for this variant. Literature search returned zero PMIDs mentioning NM_001128849.1:c.2764T>A. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available.
PS4 No prevalence data comparing affected individuals versus controls is available for this variant. It is absent from ClinVar and COSMIC. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar and COSMIC
  • no case-control data available.
Still missing
  • No affected individual counts or case-control studies available.
Sources
clinvar ↗
PM6 No de novo observation (even without paternity/maternity confirmation) has been reported for this variant. Literature search returned zero PMIDs. Details ▾Hide ▴
Still missing
  • No de novo reports available.
PP1 No cosegregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP4 No patient phenotype or family history data are available for this variant. PP4 requires a phenotype highly specific for a disease with single genetic etiology. Details ▾Hide ▴
Still missing
  • No patient phenotype data available.
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no publications mention it. Details ▾Hide ▴
Evidence considered
  • Variant absent from all evidence sources
  • no prior assertion of pathogenicity.
Still missing
  • No prior pathogenic assertion from any source.
Sources
clinvar ↗
BS2 No observation data in healthy adults with expected full penetrance at early age is available. The variant is absent from all population databases. Details ▾Hide ▴
Still missing
  • No observation data in healthy adult carriers.
BS3 No well-established in vitro or in vivo functional studies showing no damaging effect are available for this variant. Literature search returned zero PMIDs. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available.
BS4 No segregation data in affected family members is available. Literature search returned zero PMIDs for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP2 No data on trans or cis configuration with a pathogenic variant is available for this variant. Details ▾Hide ▴
Still missing
  • No phase data available.
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no prior benign assertion from any source.
Still missing
  • No prior benign classification from any source.
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no publications reference it. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar with no prior pathogenic assertions.
Still missing
  • No prior pathogenic classification from any source.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001128849.1:c.2764T>A is a missense variant (p.Trp922Arg). The generic PVS1 framework (PMC6185798) is limited to null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, exon deletions). This missense variant does not fall into any PVS1 null-variant bucket. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant eligible for PVS1 under PMC6185798.
Sources
pvs1_generic_framework ↗
PM3 N/ASMARCA4-associated conditions are autosomal dominant; PM3 (recessive disorder trans configuration) is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is a single-nucleotide substitution, not a protein-length-altering in-frame deletion or insertion. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator pathogenic missense variants identified. PM5 candidate search was unable to confirm eligible same-residue candidates; automatic harvesting skipped. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at Trp922 identified for PM5 comparison.
BP3 N/AVariant is a single-nucleotide substitution, not an in-frame deletion or insertion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_001128849.1:c.2764T>A is a missense variant (p.Trp922Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is for synonymous variants only.

Identifiers

Gene
SMARCA4
Transcript
NM_001128849.1
Coding (HGVS c.)
NM_001128849.1:c.2764T>A
Protein (HGVS p.)
NP_001122321.1:p.(Trp922Arg)
GRCh38
chr19:11021872 T>A
GRCh37
chr19:11132548 T>A

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -18 bp
0.000
SpliceAI acceptor gainat -374 bp
0.000
SpliceAI donor lossat -79 bp
0.000
SpliceAI donor gainat +133 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.948
BayesDel
0.503

How the predictions were used

PP3 SupportingMultiple lines of in silico computational evidence support a deleterious effect: REVEL score 0.948 (strongly damaging prediction) and BayesDel score 0.503 (damaging prediction, above the 0.27 threshold). SpliceAI predicts no splicing impact (max delta 0.00). The preponderance of computational evidence supports pathogenicity at supporting strength. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.948 (damaging
  • threshold >0.75).
  • BayesDel score 0.503 (damaging
  • threshold >0.27).
  • SpliceAI max delta 0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
BP4 Multiple lines of computational evidence suggest a deleterious effect, not a benign one. REVEL score 0.948 (damaging) and BayesDel score 0.503 (damaging) contradict BP4. SpliceAI max delta 0.00 indicates no splicing defect, but the preponderance of in silico evidence points toward pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.948 (damaging) opposes benign prediction.
  • BayesDel 0.503 (damaging) opposes benign prediction.
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_001128849.1:c.2764T>A is a missense variant (p.Trp922Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is for synonymous variants only.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.948. BayesDel score = 0.502973.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.948. BayesDel score = 0.502973.

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.