rs1555881572

Variant names:

• chr22-23833682-G-A
• rs1555881572
• NM_003073.5:c.1097G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-23833682-G-A
• chr22-23833682-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_003073.5(SMARCB1):​c.1097G>A​(p.Arg366His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.68

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 22) in uniprot entity SNF5_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23833681-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.1097G>A	p.Arg366His	missense_variant	Exon 8 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.1151G>A	p.Arg384His	missense_variant	Exon 8 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.1124G>A	p.Arg375His	missense_variant	Exon 8 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.1070G>A	p.Arg357His	missense_variant	Exon 8 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1097G>A	p.Arg366His	missense_variant	Exon 8 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 366 of the SMARCB1 protein (p.Arg366His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCB1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg366 amino acid residue in SMARCB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23906836). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;D;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.4	.;M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.4	D;.;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.022	D;.;D;.
Sift4G	Uncertain	0.0070	D;.;D;.
Polyphen		1.0	.;D;D;.
Vest4		0.72
MutPred		0.58		.;.;Loss of MoRF binding (P = 0.0439);.;
MVP		0.89
MPC		2.8
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.65
gMVP		0.97

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: rs1555881572; hg19: chr22-24175869; COSMIC: COSV99320434; COSMIC: COSV99320434;