rs1555881563

Positions:

• chr22-23833648-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003073.5(SMARCB1):​c.1066_1067del​(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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 [Pathogenic]. Clinvar id is 532963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.1066_1067del	p.Leu356AspfsTer4	frameshift_variant	8/9	ENST00000644036.2
SMARCB1	NM_001007468.3	c.1039_1040del	p.Leu347AspfsTer4	frameshift_variant	8/9
SMARCB1	NM_001317946.2	c.1093_1094del	p.Leu365AspfsTer4	frameshift_variant	8/9
SMARCB1	NM_001362877.2	c.1120_1121del	p.Leu374AspfsTer4	frameshift_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1066_1067del	p.Leu356AspfsTer4	frameshift_variant	8/9		NM_003073.5	A1

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: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory Division, Turku University Hospital

Aug 17, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 532963). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555881563; hg19: chr22-24175835;