NM_003073.4:c.1120C>T

SMARCB1 · NP_003064.2:p.(Arg374Trp) · NM_003073.4

GRCh37: chr22:24176329 C>T · GRCh38: chr22:23834142 C>T

Gene: SMARCB1 Transcript: NM_003073.4

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM5 moderate PP3 supporting

Variant details

Gene

SMARCB1

Transcript

NM_003073.4

Protein

NP_003064.2:p.(Arg374Trp)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	PMID:23906836 PMID:26364901 PMID:31273213
PS2	Not assessed	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.	PMID:30555950
PS3	Not met	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.	oncokb
PS4	Not met	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.	PMID:30555950
PS5	Not assessed	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.	clinvar
PM1	Met	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.	PMID:23906836 PMID:31273213
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Met	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.	PMID:23906836 PMID:26364901 PMID:31273213
PM6	Not met	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.	PMID:30555950
PP1	Not assessed	No segregation data is available for NM_003073.4:c.1120C>T. The single case report (PMID:30555950) does not describe family segregation analysis.
PP2	Not assessed	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.
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.	PMID:30555950
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	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.	revel bayesdel
BS4	Not assessed	BS4 requires lack of segregation in affected family members. No family segregation data is available for this variant.
BP1	Not met	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.	PMID:23906836 PMID:26364901
BP2	Not met	BP2 requires observation in trans with a known pathogenic variant for a fully penetrant dominant disorder. No such observation exists for this variant.
BP3	N/A	SKIP: In-frame deletions/insertions in repetitive regions not applicable to missense substitutions.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 is specific to synonymous variants. NM_003073.4:c.1120C>T is a missense variant (p.Arg374Trp), not synonymous.

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