22-23791820-G-T

Variant names:

• chr22-23791820-G-T
• rs779769475
• NM_003073.5:c.158G>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_003073.5(SMARCB1):​c.158G>T​(p.Arg53Leu) variant causes a missense 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 5.24

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 13 ACMG points.

• PM1: In a region_of_interest DNA-binding (size 112) in uniprot entity SNF5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 22-23791820-G-T is Pathogenic according to our data. Variant chr22-23791820-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.158G>T	p.Arg53Leu	missense_variant	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/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 53 of the SMARCB1 protein (p.Arg53Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with schwannomatosis (PMID: 18647326; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410706). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SMARCB1 function (PMID: 22949514, 26073604). For these reasons, this variant has been classified as Pathogenic. -

May 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: unable to rescue SMARCB1 null Drosophila specimens (PMID: 22949514; Walker, James A, Developing a Drosophila Model of Schwannomatosis 5f https://api.semanticscholar.org/CorpusID:10001485); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25772157, 26073604, 22949514, 24933152, 31586052, 29907796, 18647326) -

SMARCB1-related disorder Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMARCB1 c.158G>T variant is predicted to result in the amino acid substitution p.Arg53Leu. This variant was reported in individuals with schwannomatosis (Boyd et al., 2008. PubMed ID: 18647326; Smith et al., 2012. PubMed ID: 22949514). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 19, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R53L variant (also known as c.158G>T), located in coding exon 2 of the SMARCB1 gene, results from a G to T substitution at nucleotide position 158. The arginine at codon 53 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in multiple unrelated families with schwannomatosis and segregated with disease in 4/4 affected relatives in one family (Boyd C et al. Clin Genet, 2008 Oct;74:358-66; Ambry internal data). Tumors analyzed from affected individuals has shown either loss of heterozygosity (wild type G allele) or deletion of the region encompassing SMARCB1 and NF2 along with third mutational events in NF2 (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Missense and in-frame variants in SMARCB1 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome 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 likely pathogenic for SMARCB1-related tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

SMARCB1-related schwannomatosis Uncertain:1

-

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;T;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.6	D;.;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0060	D;.;D;D;D;D
Sift4G	Uncertain	0.0080	D;.;D;D;D;D
Polyphen		0.34, 0.85, 0.99	.;B;P;.;.;D
Vest4		0.52
MutPred		0.53		Loss of MoRF binding (P = 0.0263);Loss of MoRF binding (P = 0.0263);Loss of MoRF binding (P = 0.0263);Loss of MoRF binding (P = 0.0263);Loss of MoRF binding (P = 0.0263);Loss of MoRF binding (P = 0.0263);
MVP		0.96
MPC		1.7
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.57
gMVP		0.96

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: rs779769475; hg19: chr22-24134007;