About SMARCB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMARCB1 c.1120C>T, p.(Arg374Trp)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PM1Moderate
PM1 · moderate
This variant is located at codon Arg374 in exon 9 of SMARCB1, within the C-terminal region adjacent to the SNF5 functional domain (sucrose non-fermenting domain 5). Multiple publications establish that missense mutations clustered in exons 8 and 9 of SMARCB1 cause Coffin-Siris syndrome (CSS). CancerHotspots.org identifies this residue as lying in a statistically significant mutational hotspot. The SNF5 domain is a well-characterized functional domain essential for chromatin remodeling activity, and the variant is in a region with no described benign variation.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,590,376 alleles, including 0/1,168,738 non-Finnish European alleles), well below the 0.1% threshold for PM2. Absence from large population databases in a gene where missense variation is constrained supports pathogenicity.
PM5Moderate
PM5 · moderate
A different missense change at the same amino acid residue (p.Arg374Gln, c.1121G>A) has been reported as a de novo pathogenic variant in multiple unrelated individuals with Coffin-Siris syndrome (PMID:23906836, patient K2426; PMID:26364901; PMID:31273213, patients 1, 8, and 11). The p.Arg374Gln variant is described as affecting an evolutionarily highly conserved amino acid in close proximity to the SNF5 domain. This satisfies PM5: novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP3Supporting
PP3 · supporting
Multiple in silico tools support a deleterious effect. REVEL score is 0.861 (well above the 0.5 damaging threshold). BayesDel score is 0.50247 (above the 0.27 threshold). SpliceAI predicts no significant splice impact (max delta 0.01). The variant lies in a statistically significant mutational hotspot (CancerHotspots.org). The combination of in silico evidence supports a damaging effect on protein structure/function.
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: PM1 moderate, PM2 moderate, PM5 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, 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
0 / 1,590,376 alleles
gnomAD v4.1: 0 / 1,590,376 alleles. Recorded AF 0. Recorded homozygote count 0.
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.
ClinVar submissions
6 reported laboratory submissions
3 Uncertain significance · 2 Likely pathogenic · 1 Pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; 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 lies 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.
27 criteria with recorded statuses: 4 met · 13 not met · 7 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
NM_003073.4:c.1120C>T (p.Arg374Trp) is a missense variant in exon 9 of SMARCB1. This variant is absent from gnomAD population databases (0/1,590,376 alleles), supporting moderate evidence for pathogenicity (PM2).
The variant is located at codon Arg374 within a statistically significant mutational hotspot (CancerHotspots.org), adjacent to the SNF5 functional domain. SMARCB1 missense mutations clustered in exons 8 and 9 are an established cause of Coffin-Siris syndrome (PM1).
A different missense change at the same residue, p.Arg374Gln (c.1121G>A), has been reported as a de novo pathogenic variant in multiple unrelated individuals with Coffin-Siris syndrome in three independent publications, satisfying PM5.
Multiple in silico tools predict a deleterious effect: REVEL score 0.861 (damaging) and BayesDel score 0.50247 (damaging), supporting a pathogenic role (PP3).
The exact variant NM_003073.4:c.1120C>T has been reported in one individual with schwannomatosis and possible attenuated Coffin-Siris phenotype (PMID:30555950). No functional studies, de novo confirmation, or segregation data are available for this variant.
Applying generic ACMG/AMP 2015 criteria: PM1 (moderate) + PM2 (moderate) + PM5 (moderate) + PP3 (supporting). This combination does not meet the threshold for Likely Pathogenic (requires ≥2 strong or 1 strong + ≥3 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 4
PM1 ModerateThis variant is located at codon Arg374 in exon 9 of SMARCB1, within the C-terminal region adjacent to the SNF5 functional domain (sucrose non-fermenting domain 5). Multiple publications establish that missense mutations clustered in exons 8 and 9 of SMARCB1 cause Coffin-Siris syndrome (CSS). CancerHotspots.org identifies this residue as lying in a statistically significant mutational hotspot. The SNF5 domain is a well-characterized functional domain essential for chromatin remodeling activity, and the variant is in a region with no described benign variation. Details ▾Hide ▴
Evidence considered
- Residue lies in a statistically significant hotspot (CancerHotspots.org)
- located in exon 9 adjacent to SNF5 functional domain
- SMARCB1 missense mutations in exons 8-9 are established as causative for CSS.
Sources
PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,590,376 alleles, including 0/1,168,738 non-Finnish European alleles), well below the 0.1% threshold for PM2. Absence from large population databases in a gene where missense variation is constrained supports pathogenicity. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- absent from gnomAD v4.1 (0/1
- 590
- 376 alleles
- joint AF=0.0). Well below PM2 threshold of <0.1%.
Sources
PM5 ModerateA different missense change at the same amino acid residue (p.Arg374Gln, c.1121G>A) has been reported as a de novo pathogenic variant in multiple unrelated individuals with Coffin-Siris syndrome (PMID:23906836, patient K2426; PMID:26364901; PMID:31273213, patients 1, 8, and 11). The p.Arg374Gln variant is described as affecting an evolutionarily highly conserved amino acid in close proximity to the SNF5 domain. This satisfies PM5: novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Details ▾Hide ▴
Evidence considered
- p.Arg374Gln (c.1121G>A) reported as de novo pathogenic in CSS patients in three independent publications
- same residue different amino acid change satisfies PM5.
Sources
PP3 SupportingMultiple in silico tools support a deleterious effect. REVEL score is 0.861 (well above the 0.5 damaging threshold). BayesDel score is 0.50247 (above the 0.27 threshold). SpliceAI predicts no significant splice impact (max delta 0.01). The variant lies in a statistically significant mutational hotspot (CancerHotspots.org). The combination of in silico evidence supports a damaging effect on protein structure/function. Details ▾Hide ▴
Evidence considered
- REVEL 0.861 (damaging)
- BayesDel 0.50247 (damaging)
- SpliceAI max delta 0.01 (no splice impact)
- residue in statistically significant hotspot.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change as an established pathogenic variant. No pathogenic variant with the same amino acid change (p.Arg374Trp) has been identified. The known pathogenic variant at this residue is p.Arg374Gln (c.1121G>A), a different amino acid substitution, which is assessed under PM5 instead. Details ▾Hide ▴
Evidence considered
- Literature review identified p.Arg374Gln (c.1121G>A) at the same codon
- not p.Arg374Trp. No variant with the identical amino acid change is reported as pathogenic.
Sources
PS3 No variant-specific functional assay data exists for NM_003073.4:c.1120C>T (p.Arg374Trp). The literature contains no experimental functional characterization of this exact variant. OncoKB assigns a 'Likely Oncogenic' label based on curated knowledge, but this is a somatic oncogenicity designation and does not constitute germline functional evidence for PS3. No systematic range characterization (tiling screen, saturation mutagenesis, truncation series) including this position was identified. Details ▾Hide ▴
Evidence considered
- OncoKB curated label of 'Likely Oncogenic' is noted but does not substitute for variant-specific germline functional data
- no primary functional assay identified for this variant.
Still missing
- No variant-specific or systematic-range functional data available for p.Arg374Trp.
Sources
PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. Only one published case of NM_003073.4:c.1120C>T has been identified (PMID:30555950: a 28-year-old female with schwannomatosis and possible attenuated Coffin-Siris phenotype). A single case report does not meet the threshold for PS4. Details ▾Hide ▴
Evidence considered
- One affected individual reported in the literature with schwannomatosis and possible attenuated CSS phenotype.
Still missing
- Additional case reports or case-control data would be needed to support PS4.
Sources
PM6 PM6 requires a de novo observation with confirmed maternity and paternity. No de novo data exists for NM_003073.4:c.1120C>T. The case report in PMID:30555950 does not describe parental testing or confirm de novo status. Details ▾Hide ▴
Evidence considered
- No de novo confirmation with parental testing available for this variant.
Still missing
- Parental testing not performed in the single reported case (PMID:30555950).
Sources
PP5 PP5 requires a reputable source (ClinVar 3-star expert panel or equivalent) reporting the variant as pathogenic. The ClinVar review status for this variant (ClinVar ID 633561) is 'criteria provided, single submitter' (1-star), with no expert panel submissions. Per the governing framework, PP5 is only applied at supporting strength when ClinVar has 3-star expert panel status; 1-star review status does not satisfy this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar aggregation: 3 VUS
- 2 Likely Pathogenic
- 1 Pathogenic
- review status 'criteria provided
- single submitter' (1-star)
- no expert panel submissions
- does not meet 3-star EP threshold for PP5.
Sources
BA1 BA1 requires an allele frequency >1% in population databases. This variant is absent from gnomAD v4.1 (0/1,590,376 alleles). Does not meet the >1% threshold. Details ▾Hide ▴
BS1 BS1 requires an allele frequency >0.3% in population databases. This variant is absent from gnomAD v4.1 (0/1,590,376 alleles). Does not meet the >0.3% threshold. Details ▾Hide ▴
BS2 BS2 requires observation in a healthy adult in the homozygous or hemizygous state, or in trans with a pathogenic variant. This variant is absent from gnomAD with zero homozygotes. No healthy adult homozygous or hemizygous observation exists. Details ▾Hide ▴
BS3 BS3 requires well-established functional studies showing no damaging effect on protein function or splicing. No functional data exists for NM_003073.4:c.1120C>T. In silico predictions (REVEL 0.861, BayesDel 0.50247) suggest a damaging rather than benign effect. Details ▾Hide ▴
Evidence considered
- No functional data exists
- in silico tools predict a damaging effect (REVEL 0.861).
Still missing
- No functional characterization of this variant available.
Sources
revelbayesdel
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. SMARCB1 missense variants in exons 8-9 are a well-established disease mechanism for Coffin-Siris syndrome. Missense variants in SMARCB1 are also associated with schwannomatosis. Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- SMARCB1 missense variants in exons 8-9 are a known disease mechanism for CSS
- missense variants also cause schwannomatosis. BP1 is not applicable when missense is a known disease mechanism.
Sources
BP2 BP2 requires observation in trans with a known pathogenic variant for a fully penetrant dominant disorder. No such observation exists for this variant. Details ▾Hide ▴
Evidence considered
- No observation in trans with a pathogenic variant reported.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.861 strongly predicts a damaging effect. SpliceAI max delta of 0.01 suggests no splice impact, but the REVEL and BayesDel scores point toward a deleterious effect, not a benign one. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.861 (damaging) and BayesDel 0.50247 (damaging) contradict BP4
- SpliceAI 0.01 suggests no splice impact but overall in silico evidence supports damaging rather than benign.
Sources
BP6 BP6 requires a reputable source (ClinVar 3-star expert panel) reporting the variant as benign. The ClinVar review status for this variant is 'criteria provided, single submitter' (1-star), with no benign classifications (classifications are VUS, Likely Pathogenic, and Pathogenic). No expert panel has classified this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar status 1-star
- no benign classifications
- does not meet BP6 requirement.
Sources
Not assessed · 7 · no assessment recorded
PS2 No de novo data for NM_003073.4:c.1120C>T was identified in the literature. The only case report (PMID:30555950) does not report parental testing to establish de novo status. Details ▾Hide ▴
Evidence considered
- One case report describes the variant but does not document de novo occurrence
- no parental testing was performed.
Still missing
- No de novo confirmation data available for this variant.
Sources
PP1 No segregation data is available for NM_003073.4:c.1120C>T. The single case report (PMID:30555950) does not describe family segregation analysis. Details ▾Hide ▴
Evidence considered
- No segregation analysis available.
Still missing
- Family segregation data would be needed to assess PP1.
PP2 PP2 requires a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. While SMARCB1 missense variants in exons 8-9 are a known disease mechanism for CSS, a systematic assessment of the gene-level missense constraint metric (e.g., gnomAD missense Z-score or o/e score) was not available in the evidence packet to confirm a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- SMARCB1 missense variants in exons 8-9 are established CSS mechanism
- but gene-level missense constraint metrics not available for systematic PP2 assessment.
Still missing
- gnomAD missense constraint metric (Z-score) needed for PP2 assessment.
PP4 PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. The specific phenotype of the proband under assessment is not documented in the case materials. The single literature case (PMID:30555950) describes schwannomatosis with possible attenuated CSS features, but without detailed phenotypic data for a systematic PP4 assessment. Details ▾Hide ▴
Evidence considered
- Literature case has schwannomatosis with possible attenuated CSS
- proband phenotype not provided in case materials.
Still missing
- Proband clinical phenotype needed for PP4 assessment.
Sources
BS4 BS4 requires lack of segregation in affected family members. No family segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Family segregation data not available.
BP5 BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No such data is available in the case materials. Details ▾Hide ▴
Evidence considered
- No evidence of alternate molecular diagnosis in the proband.
Still missing
- Proband clinical and molecular data not available for BP5 assessment.
PS5 PS5 is intended for a reputable source report of pathogenicity where the supporting evidence is not available for independent review. There are ClinVar submitters who classify this variant as Pathogenic or Likely Pathogenic, but the variant is not from a 3-star expert panel source, and primary literature with variant-level evidence is available for independent review. This criterion is not assessed independently. Details ▾Hide ▴
Evidence considered
- ClinVar submissions include Pathogenic (1 lab) and Likely Pathogenic (2 labs) classifications from clinical testing laboratories with criteria provided
- single submitter review status.
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_003073.4:c.1120C>T is a missense change (p.Arg374Trp) in exon 9 of 9 and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants defined by the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant does not qualify for PVS1 null-variant assessment per PMC6185798
- apply_generic_pvs1_framework is false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP3 N/ASKIP: In-frame deletions/insertions in repetitive regions not applicable to missense substitutions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is specific to synonymous variants. NM_003073.4:c.1120C>T is a missense variant (p.Arg374Trp), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Identifiers
- Gene
- SMARCB1
- Transcript
- NM_003073.4
- Coding (HGVS c.)
- NM_003073.4:c.1120C>T
- Protein (HGVS p.)
- NP_003064.2:p.(Arg374Trp)
- GRCh38
- chr22:23834142 C>T
- GRCh37
- chr22:24176329 C>T
- ClinVar
- 4170240, 633561
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…
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 SMARCB1
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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
0 / 1,590,376 alleles
AF 0 · 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 0 · 0 / 1,590,376 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1590376 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74292 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
- 0.861
- BayesDel
- 0.502
How the predictions were used
PP3 SupportingMultiple in silico tools support a deleterious effect. REVEL score is 0.861 (well above the 0.5 damaging threshold). BayesDel score is 0.50247 (above the 0.27 threshold). SpliceAI predicts no significant splice impact (max delta 0.01). The variant lies in a statistically significant mutational hotspot (CancerHotspots.org). The combination of in silico evidence supports a damaging effect on protein structure/function. Details ▾Hide ▴
Evidence considered
- REVEL 0.861 (damaging)
- BayesDel 0.50247 (damaging)
- SpliceAI max delta 0.01 (no splice impact)
- residue in statistically significant hotspot.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.861 strongly predicts a damaging effect. SpliceAI max delta of 0.01 suggests no splice impact, but the REVEL and BayesDel scores point toward a deleterious effect, not a benign one. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.861 (damaging) and BayesDel 0.50247 (damaging) contradict BP4
- SpliceAI 0.01 suggests no splice impact but overall in silico evidence supports damaging rather than benign.
Sources
BP7 N/ABP7 is specific to synonymous variants. NM_003073.4:c.1120C>T is a missense variant (p.Arg374Trp), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.861. BayesDel score = 0.50247.
6 paper records listed. 3 cited in the classification.
Cited in the classification
-
PMID 23906836 ↗A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.Wieczorek D et al. · 2013 Dec 20Large molecular study of Coffin-Siris and Nicolaides-Baraitser syndromes. Identifies a de novo missense mutation c.1121G>A (p.Arg374Gln) in SMARCB1 in individual K2426 with CSS. Also identifies a de novo missense c.1096C>T (p.Arg366Cys) in individual K2588. Neither is c.1120C>T (p.Arg374Trp). The p.Arg374Gln variant is described as located in exon 9 near the SNF5 domain, affecting an evolutionarily highly conserved amino acid.→ PM1 → PM5 Does not name this variant
Source detail
The de novo missense mutation p.Arg374Gln in SMARCB1 is located within exon 9 of the gene and leads to the substitution of an evolutionary highly conserved amino acid in close proximity of the sucrose non-fermenting domain 5 (SNF5) of the protein, likely affecting domain structure.
Location Results section; Table 1; Figure 2
Context Whole-exome sequencing, NGS-based panel sequencing of 23 SWI/SNF genes, molecular karyotyping; no functional assay performed on this variant.
-
PMID 26364901 ↗Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.Gossai N et al. · 2015 DecDescribes a 33-year-old man with Coffin-Siris syndrome and schwannomatosis carrying a different missense variant at the same codon: NM_003073.4:c.1121G>A (p.Arg374Gln). This is not the variant under assessment (c.1120C>T, p.Arg374Trp). The paper reports the SMARCB1 missense as germline with tumor-acquired loss of 22q including SMARCB1 and NF2, completing the four-hit mechanism of schwannomatosis.→ PM5 Does not name this variant
Source detail
SMARCB1 gene testing of peripheral blood revealed a missense mutation in exon 9, c.1121G>A (p.Arg374Gln).
Location Clinical Report paragraph 1; Discussion paragraph 2
Context Clinical case report; germline sequencing, tumor comparative genomic hybridization, NF2 gene testing.
-
PMID 31273213 ↗Mutations in SMARCB1 and in other Coffin-Siris syndrome genes lead to various brain midline defects.Filatova A et al. · 2019 Jul 4Mouse model study of Smarcb1 heterozygous disruption in neural stem cells, with correlation to CSS patient brain midline defects. Table 1 lists three CSS patients with c.1121G>A p.(Arg374Gln) in SMARCB1 (Patients 1, 8, 11), a different variant at the same residue as c.1120C>T. The paper demonstrates that SMARCB1 mutations cause brain midline defects including corpus callosum agenesis, hippocampal commissure absence, and choroid plexus hyperplasia. No functional data on p.Arg374Trp.→ PM1 → PM5 Does not name this variant
Source detail
1 c.1121G>A p.(Arg374Gln) SMARCB1
Location Table 1
Context Mouse model (Smarcb1+/inv NesCre) with conditional exon 1 inversion; human MRI review of CSS patients; no variant-specific functional assay.
Other 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 standards and guidelines for interpretation of sequence variants (Richards et al. 2015). This is the foundational framework document for variant classification and does not discuss any specific variants. Cited as the source of the generic ACMG/AMP classification framework used in this assessment.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. This is a clinical practice document that does not discuss any specific SMARCB1 variants or mention NM_003073.4:c.1120C>T. The paper provides general referral criteria for hereditary cancer syndromes.Does not name this variant
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PMID 30555950 ↗Simple schwannomatosis or an incomplete Coffin-Siris? Report of a particular case.Bellantoni G et al. · 2019NM_003073.4:c.1120C>T (p.R374W) identified in a 28-year-old female with schwannomatosis, Sjogren syndrome, and spontaneous splenic rupture from a wandering spleen. The patient lacked full Coffin-Siris syndrome features (no ectodermal anomalies, no intellectual disability) but had mild cardiac valvular insufficiency. Authors note this mutation has never been described before and suggest it may represent an attenuated CSS phenotype.Names this variant
Quoted passage
They revealed the mutation c.1120C > T (p.R374W) of gene SMARCB1 in chromosome 22; no puntiform mutations in NF1 and NF2 locus gene were found.
Case description paragraph 1
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,590,376 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 · 2 Likely pathogenic · 1 Pathogenic
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/633561/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-24176329-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-23834142-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/22-23834142-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003073.4%3Ac.1120…
- OncoKB ↗www.oncokb.org/gene/SMARCB1/R374W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SMARCB1+c.1120C%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= 0; MAF= 0.00000%, 0/1590376 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74292 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 (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 633561)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.861. BayesDel score = 0.50247.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.