rs1555881563

Variant names:

• chr22-23833648-ACT-A
• rs1555881563
• NM_003073.5:c.1066_1067delCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003073.5(SMARCB1):​c.1066_1067delCT​(p.Leu356AspfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L356L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.66
• Publications: 1 publications found

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schwannomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-23833648-ACT-A is Pathogenic according to our data. Variant chr22-23833648-ACT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532963.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.1066_1067delCT	p.Leu356AspfsTer4	frameshift_variant	Exon 8 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.1120_1121delCT	p.Leu374AspfsTer4	frameshift_variant	Exon 8 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.1093_1094delCT	p.Leu365AspfsTer4	frameshift_variant	Exon 8 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.1039_1040delCT	p.Leu347AspfsTer4	frameshift_variant	Exon 8 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1066_1067delCT	p.Leu356AspfsTer4	frameshift_variant	Exon 8 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:1

Aug 17, 2022

Laboratory Division, Turku University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG class 5: pathogenic (PVS1, PS2, PM2). Variant was absent from parents indicating a de novo origin. The discovered SMARCB1-variant was rare as it was not reported in the Genome Aggregation Database (GnomAD) or in literature. However, this variant was recently reported in Clinical Variant Database as a likely pathogenic variant (ClinVar: VCV000532963.5) -

not provided Pathogenic:1

Jan 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu356Aspfs*4) in the SMARCB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the SMARCB1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532963). This variant disrupts a region of the SMARCB1 protein in which other variant(s) ( p.Thr357Ile, p.Arg374Gln, p.Arg377His) have been determined to be pathogenic (PMID: 22426308, 23906836, 25169651, 26364901; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1066_1067delCT variant, located in coding exon 8 of the SMARCB1 gene, results from a deletion of two nucleotides at nucleotide positions 1066 to 1067, causing a translational frameshift with a predicted alternate stop codon (p.L356Dfs*4). This alteration occurs at the 3' terminus of SMARCB1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and impacts the last 7.77% of the protein. The exact functional effect of this alteration is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555881563; hg19: chr22-24175835; COSMIC: COSV51954465;