rs74315513

chr22-23787203-C-T

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.34C>T(p.Gln12Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.79

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 68 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-23787203-C-T is Pathogenic according to our data. Variant chr22-23787203-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23787203-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.34C>T	p.Gln12Ter	stop_gained	1/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.34C>T	p.Gln12Ter	stop_gained	1/9
SMARCB1	NM_001317946.2	c.34C>T	p.Gln12Ter	stop_gained	1/9
SMARCB1	NM_001007468.3	c.34C>T	p.Gln12Ter	stop_gained	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.34C>T	p.Gln12Ter	stop_gained	1/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schwannomatosis 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 8026). This premature translational stop signal has been observed in individual(s) with SMARCB1-related schwannomatosis (PMID: 17357086). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln12*) in the SMARCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMARCB1 are known to be pathogenic (PMID: 10521299, 21208904). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

The p.Q12* pathogenic mutation (also known as c.34C>T), located in coding exon 1 of the SMARCB1 gene, results from a C to T substitution at nucleotide position 34. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration has been reported in several individuals with multiple schwannomas and/or clinical diagnoses of schwannomatosis (Hulsebos TJ et al. Am J Hum Genet, 2007 Apr;80:805-10; Smith MJ et al. Neurogenetics, 2012 May;13:141-5; Louvrier C et al. Neuro Oncol, 2018 Jun;20:917-929; Rousseau G et al. BMC Neurol, 2011 Jan;11:9; Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in SMARCB1 are known to cause rhabdoid tumor predisposition syndrome; however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Eaton KW et al. Pediatr Blood Cancer. 2011 Jan;56(1):7-15). Based on the supporting evidence, this alteration is pathogenic for SMARCB1-related tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	47
Dann	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.81
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74315513; hg19: chr22-24129390;