NM_003073.5:c.582G>C

Variant names:

• chr22-23803376-G-C
• rs759241720
• NM_003073.5:c.582G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003073.5(SMARCB1):​c.582G>C​(p.Glu194Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E194E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.582G>C	p.Glu194Asp	missense_variant	Exon 5 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.636G>C	p.Glu212Asp	missense_variant	Exon 5 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.609G>C	p.Glu203Asp	missense_variant	Exon 5 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.555G>C	p.Glu185Asp	missense_variant	Exon 5 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.582G>C	p.Glu194Asp	missense_variant	Exon 5 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 571583). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This sequence change replaces glutamic acid with aspartic acid at codon 194 of the SMARCB1 protein (p.Glu194Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;T;T;.;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	.;L;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.5	N;.;N;.;.;N
REVEL	Uncertain	0.41
Sift	Benign	0.45	T;.;T;.;.;T
Sift4G	Uncertain	0.016	D;.;D;.;.;D
Polyphen		0.019, 0.013, 0.059	.;B;B;.;.;B
Vest4		0.74
MutPred		0.90		.;.;Gain of ubiquitination at K208 (P = 0.1181);.;.;.;
MVP		0.89
MPC		1.3
ClinPred		0.35	T
GERP RS		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.76

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: rs759241720; hg19: chr22-24145563;