rs1555875892

Variant names:

• chr22-23791797-G-GAGAT
• rs1555875892
• NM_003073.5:c.137_140dupGATA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003073.5(SMARCB1):​c.137_140dupGATA​(p.Tyr47fs) variant causes a frameshift, stop gained change involving the alteration of a non-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, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.12

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 12 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 22-23791797-G-GAGAT is Pathogenic according to our data. Variant chr22-23791797-G-GAGAT is described in ClinVar as [Pathogenic]. Clinvar id is 464322.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.137_140dupGATA	p.Tyr47fs	frameshift_variant, stop_gained	Exon 2 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.137_140dupGATA	p.Tyr47fs	frameshift_variant, stop_gained	Exon 2 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.137_140dupGATA	p.Tyr47fs	frameshift_variant, stop_gained	Exon 2 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.137_140dupGATA	p.Tyr47fs	frameshift_variant, stop_gained	Exon 2 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.137_140dupGATA	p.Tyr47fs	frameshift_variant, stop_gained	Exon 2 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SMARCB1 are known to be pathogenic (PMID: 10521299, 21208904). A different variant, c.141C>A, with the same effect (p.Tyr47*) has been reported in an individual with rhabdoid tumors (PMID: 21108436). This sequence change inserts 4 nucleotides in exon 2 of the SMARCB1 mRNA (c.137_140dupGATA), causing a frameshift at codon 47. This creates a premature translational stop signal (p.Tyr47*) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555875892; hg19: chr22-24133984;