About SMARCA4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMARCA4 c.1333C>T, p.(Gln445Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_001128849.1:c.1333C>T is a nonsense variant (p.Gln445Ter) in exon 8 of 35 in SMARCA4, a gene in which loss of function is an established mechanism for germline disease (rhabdoid tumor predisposition syndrome type 2, Coffin-Siris syndrome). The premature stop codon at position 445 of 1,647 amino acids is predicted to trigger nonsense-mediated decay, resulting in a null allele. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with established LoF disease mechanisms qualify for PVS1 at full strength.
PM2Moderate
PM2 · moderate
NM_001128849.1:c.1333C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 criterion for absence from population databases under generic ACMG/AMP 2015 guidelines. The allele frequency of 0.0 across all queried population cohorts is well below the 0.1% threshold.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
29 criteria with recorded statuses: 2 met · 14 not met · 2 not assessed · 11 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.1333C>T (p.Gln445Ter) is a nonsense variant in exon 8 of SMARCA4, a gene with an established loss-of-function disease mechanism for rhabdoid tumor predisposition syndrome type 2 and Coffin-Siris syndrome, satisfying PVS1 at very strong strength under the ClinGen SVI framework (PMC6185798).
This variant is absent from all queried population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2 at moderate strength.
The variant is absent from ClinVar and has not been reported in any curated clinical database, consistent with a rare variant of uncertain prevalence in affected populations.
No variant-specific functional studies, de novo observations, case-control data, or cosegregation evidence were identified for this variant in the available literature.
Applying generic ACMG/AMP 2015 combination rules, the evidence totals 10 points (PVS1 very_strong = 8 points; PM2 moderate = 2 points), meeting the threshold for a Pathogenic classification (>=10 points).
No criteria match.
Met · 2
PVS1 Very strongNM_001128849.1:c.1333C>T is a nonsense variant (p.Gln445Ter) in exon 8 of 35 in SMARCA4, a gene in which loss of function is an established mechanism for germline disease (rhabdoid tumor predisposition syndrome type 2, Coffin-Siris syndrome). The premature stop codon at position 445 of 1,647 amino acids is predicted to trigger nonsense-mediated decay, resulting in a null allele. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with established LoF disease mechanisms qualify for PVS1 at full strength. Details ▾Hide ▴
Evidence considered
- Nonsense variant predicted to trigger NMD (stop codon at aa 445/1647)
- SMARCA4 has definitive germline loss-of-function disease mechanism (RTPS2
- Coffin-Siris syndrome)
- ClinGen Gene-Disease Validity classifies SMARCA4 as definitive for Coffin-Siris syndrome with LoF mechanism
Still missing
- No ClinVar record for this exact variant to corroborate pathogenicity classification
- Confirm that NM_001128849.1 is the biologically relevant transcript in the testing laboratory's context
Sources
PM2 ModerateNM_001128849.1:c.1333C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 criterion for absence from population databases under generic ACMG/AMP 2015 guidelines. The allele frequency of 0.0 across all queried population cohorts is well below the 0.1% threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles / ~250k alleles)
- Absent from gnomAD v4.1 (0 alleles / ~800k alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
Not met · 14 · evaluated, threshold not reached
PS2 No confirmed de novo observation with verified parentage was identified for NM_001128849.1:c.1333C>T in the available literature, ClinVar, or exploratory evidence search results. Details ▾Hide ▴
Evidence considered
- Exploratory search suggests a possible ClinVar record (VCV000427319) but direct query returned no results for this variant
Still missing
- No de novo report with parental confirmation found for this exact variant
- Variant may be present in LOVD or internal laboratory databases not accessible to this search
Sources
PS3 No variant-specific experimental functional studies were identified for c.1333C>T. OncoKB classifies Q445* as Likely Oncogenic/Likely Loss-of-function, but this represents a curated knowledgebase annotation based on variant type inference, not direct experimental functional evidence meeting the PS3 threshold for germline variant classification. Details ▾Hide ▴
Evidence considered
- OncoKB annotation: Likely Oncogenic
- Likely Loss-of-function (inference from nonsense variant type)
Still missing
- No ATPase activity assay
- chromatin remodeling assay
- or protein expression study performed for this exact variant
Sources
PS4 No case-control study comparing the prevalence of c.1333C>T in affected versus healthy populations is available. The variant's absence from gnomAD supports rarity but is captured under PM2 rather than PS4. The low incidence of SMARCA4-related disorders precludes formal case-control analysis. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- consistent with rarity but insufficient for PS4 without case-control data
Still missing
- No case-control study comparing variant frequency in affected cohorts versus general population
Sources
PM1 The variant at codon 445 lies in the N-terminal region of SMARCA4, outside any well-defined critical functional domain. The ATPase catalytic domain spans residues 757-1,564. The variant does not reside in a statistically significant mutational hotspot per CancerHotspots, and no variant-specific domain-based evidence supports PM1. Details ▾Hide ▴
Evidence considered
- Position 445 is N-terminal to all annotated functional domains (QLQ
- HSA
- BRK
- DEXDc
- SNF2_N
- HELICc
- Bromo
- ATPase)
- CancerHotspots: residue not significant and variant not listed
- Figure 1 of PMID:24658002 shows mutations scattered along the protein
- consistent with a tumor suppressor pattern
Sources
PMID:24658002 ↗24658002
PM6 No de novo observation (assumed or confirmed) was identified for c.1333C>T. The exploratory evidence search noted a possible ClinVar record (VCV000427319) that might contain de novo submissions, but direct ClinVar query for this variant returned no results. PM6 cannot be applied without at least one de novo report. Details ▾Hide ▴
Evidence considered
- No de novo assertion found in ClinVar or literature
Still missing
- Variant may have de novo submissions in LOVD or internal databases not accessible to this search
- Confirm whether VCV000427319 exists and contains de novo origin assertions
Sources
PP1 No published cosegregation data for c.1333C>T with disease in multiple affected family members was identified. Most SMARCA4 germline mutations reported in the literature are de novo events; familial cases with documented segregation are rare and none involve this specific variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data identified for this variant
Still missing
- No family studies with variant cosegregation
Sources
PMID:24658002 ↗24658002
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0 and does not approach the 1% BA1 threshold required for a stand-alone benign classification. Details ▾Hide ▴
Evidence considered
- Population allele frequency: 0.0 (absent)
Sources
BS1 The variant is absent from all queried population databases. Allele frequency of 0.0 does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Population allele frequency: 0.0 (absent)
Sources
BS2 No evidence of observation of c.1333C>T in healthy adults was identified. The variant is absent from all population databases including gnomAD, which includes ostensibly healthy individuals. Details ▾Hide ▴
BS3 No well-established functional studies demonstrating a neutral or benign effect were identified for c.1333C>T. The five literature_pass papers (PMID:18301784, 24658001, 24658002, 24658004, 25060813) discuss SMARCA4 at the gene level without providing variant-specific benign functional evidence. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional data found
Still missing
- No experimental functional assay demonstrating normal protein function for this variant
Sources
BS4 No evidence of non-segregation with disease was identified. BS4 requires documentation that an affected individual does not carry the variant, which is not available. Details ▾Hide ▴
Still missing
- No non-segregation data for this variant
BP2 No observation of c.1333C>T in trans with a known pathogenic SMARCA4 variant in a healthy individual has been reported. Furthermore, SMARCA4-related disorders exhibit incomplete penetrance and variable expressivity, limiting the applicability of BP2 even if such an observation were available. Details ▾Hide ▴
Still missing
- No observation of variant in trans with another pathogenic variant in an unaffected individual
BP4 Multiple lines of computational evidence do not suggest a benign effect. The BayesDel score of 0.66 exceeds the deleterious threshold (>0.5), arguing against BP4. SpliceAI predicts no splicing impact (max delta = 0.01), but this alone is insufficient to satisfy the multiple-lines-of-evidence requirement for BP4. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.66 (deleterious
- not benign)
- SpliceAI max delta: 0.01 (neutral
- but insufficient to offset BayesDel)
Sources
bayesdelspliceai ↗
BP5 No observation of c.1333C>T in a case with an alternate molecular basis for disease was identified. BP5 requires a documented alternate cause in an affected individual carrying this variant. Details ▾Hide ▴
Still missing
- No co-occurrence data with another molecular diagnosis
Not assessed · 2 · no assessment recorded
PP3 For a nonsense variant, the deleterious effect is already captured by PVS1. BayesDel score of 0.66 for this position is above the deleterious threshold, and SpliceAI predicts no splicing impact (max delta = 0.01). In silico scores for a nonsense variant are considered redundant with PVS1 and are not independently applied under standard ACMG/AMP practice to avoid double-counting. Details ▾Hide ▴
Evidence considered
- BayesDel score: 0.66 (deleterious prediction)
- SpliceAI max delta: 0.01 (no splicing impact)
Sources
bayesdelspliceai ↗
PP4 No patient-specific phenotype or family history information was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical data. Details ▾Hide ▴
Still missing
- No clinical phenotype data provided for this case
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a different amino acid change at the same residue as a known pathogenic missense variant. This is a nonsense variant (p.Gln445Ter); no same-residue missense comparator is applicable. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. SMARCA4-related conditions (RTPS2, Coffin-Siris syndrome) are autosomal dominant; PM3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to nonstop or elongation variants resulting from stop-loss or in-frame changes. This is a substitution variant causing a premature stop codon (nonsense), not protein elongation. PM4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. This variant is nonsense (p.Gln445Ter); the pm5_candidates search yielded zero same-residue comparator variants and the recommendation level is not_applicable. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense comparators identified in ClinVar or literature
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense variant; PP2 is not applicable to truncating variants. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 requires a reputable source to have recently reported the variant as pathogenic. This variant is absent from ClinVar and has no prior classification from any external source. Details ▾Hide ▴
Sources
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. This variant is a truncating (nonsense) change; BP1 does not apply to null variants. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions. This is a single-nucleotide substitution variant; BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 requires a reputable source to have reported the variant as benign. This variant is absent from ClinVar and has no prior benign classification from any external source. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense (stop-gain) variant; BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 requires the variant to be reported as pathogenic by a reputable source where the evidence is not available for independent evaluation. This variant is absent from ClinVar and has no prior classification from any external source. Details ▾Hide ▴
Sources
Identifiers
- Gene
- SMARCA4
- Transcript
- NM_001128849.1
- Coding (HGVS c.)
- NM_001128849.1:c.1333C>T
- Protein (HGVS p.)
- NP_001122321.1:p.(Gln445Ter)
- GRCh38
- chr19:10991237 C>T
- GRCh37
- chr19:11101913 C>T
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
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
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
BP4 Multiple lines of computational evidence do not suggest a benign effect. The BayesDel score of 0.66 exceeds the deleterious threshold (>0.5), arguing against BP4. SpliceAI predicts no splicing impact (max delta = 0.01), but this alone is insufficient to satisfy the multiple-lines-of-evidence requirement for BP4. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.66 (deleterious
- not benign)
- SpliceAI max delta: 0.01 (neutral
- but insufficient to offset BayesDel)
Sources
bayesdelspliceai ↗
PP3 For a nonsense variant, the deleterious effect is already captured by PVS1. BayesDel score of 0.66 for this position is above the deleterious threshold, and SpliceAI predicts no splicing impact (max delta = 0.01). In silico scores for a nonsense variant are considered redundant with PVS1 and are not independently applied under standard ACMG/AMP practice to avoid double-counting. Details ▾Hide ▴
Evidence considered
- BayesDel score: 0.66 (deleterious prediction)
- SpliceAI max delta: 0.01 (no splicing impact)
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense (stop-gain) variant; BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.
5 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
-
PMID 18301784 ↗The BRG1 transcriptional coregulator.No paper-specific finding is recorded.
-
PMID 24658001 ↗Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.No paper-specific finding is recorded.
-
PMID 24658002 ↗Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.No paper-specific finding is recorded.
-
PMID 24658004 ↗Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.No paper-specific finding is recorded.
-
PMID 25060813 ↗SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis.No paper-specific finding is recorded.
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 0.010
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001128849.1%3Ac.1333C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-11101913-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-10991237-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-10991237-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001128849.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/SMARCA4/Q445*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SMARCA4+c.1333C%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
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 = 0.01). BayesDel score = 0.66.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.