22-23787248-A-G

Variant names:

• chr22-23787248-A-G
• rs762676176
• NM_003073.5:c.79A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003073.5(SMARCB1):​c.79A>G​(p.Met27Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449104 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 721572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 1 Uncertain:1

Oct 09, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 941247). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the SMARCB1 protein (p.Met27Val). -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M27V variant (also known as c.79A>G), located in coding exon 1 of the SMARCB1 gene, results from an A to G substitution at nucleotide position 79. The methionine at codon 27 is replaced by valine, an amino acid with highly similar properties. 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). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	.;D;T;.;.;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.046
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.9	L;L;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N;.;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.16	T;.;T;T;T;T
Sift4G	Benign	0.22	T;.;T;T;T;T
Polyphen		0.35, 0.071, 0.012	.;B;B;.;.;B
Vest4		0.73
MutPred		0.36		Gain of catalytic residue at M27 (P = 0.0188);Gain of catalytic residue at M27 (P = 0.0188);Gain of catalytic residue at M27 (P = 0.0188);Gain of catalytic residue at M27 (P = 0.0188);Gain of catalytic residue at M27 (P = 0.0188);Gain of catalytic residue at M27 (P = 0.0188);
MVP		0.81
MPC		1.4
ClinPred		0.94	D
GERP RS		2.4
Varity_R		0.62
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762676176; hg19: chr22-24129435;