rs1555876140

chr22-23793671-GC-Gchr22-23793671-GC-GCC

Variant summary

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

The NM_003073.5(SMARCB1):c.351del(p.Thr118ProfsTer25) 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 (★). Synonymous variant affecting the same amino acid position (i.e. P116P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCB1 NM_003073.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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 22-23793671-GC-G is Pathogenic according to our data. Variant chr22-23793671-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 692027.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-23793671-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.351del	p.Thr118ProfsTer25	frameshift_variant	3/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.351del	p.Thr118ProfsTer25	frameshift_variant	3/9
SMARCB1	NM_001317946.2	c.324del	p.Thr109ProfsTer25	frameshift_variant	3/9
SMARCB1	NM_001007468.3	c.324del	p.Thr109ProfsTer25	frameshift_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.351del	p.Thr118ProfsTer25	frameshift_variant	3/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Teratoid tumor, atypical Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

May 03, 2018

This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, pathogenic variation in SMARCB1 has been associated with Coffin-Siris syndrome 3 (MIM: 614608), rhabdoid tumor predisposition syndrome 1 (MIM: 609322), and susceptibility to schwannomatosis-1 (MIM: 162091). In particular, null variants are generally associated with rhabdoid tumors, while missense variants tend to be associated with Coffin-Siris syndrome 3 and familial schwannomatosis. This particular null variant has not been reported in affected individuals in ClinVar or HGMD, and this variant has not been observed in the gnomAD population database. This variant is predicted to result in a frameshift (in exon 3 of 9) and a premature STOP codon after 27 additional amino acids, leading to the production of truncated SMARCB1 protein likely with little or no functional activity. An additional somatic mutation in the remaining normal copy of the SMARCB1 gene would result in the development of rhabdoid tumors. Based on the combined evidence, the c.347_348delinsT Pro116Leufs*27 variant is classified as pathogenic. -

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: rs1555876140; hg19: chr22-24135858;