rs779221331

chr22-23803295-C-Gchr22-23803295-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_003073.5(SMARCB1):c.501C>G(p.Cys167Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C167C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense, splice_region
• Scores: Splicing: ADA: 0.9413
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.71

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.

• PP2: Missense variant where missense usually causes diseases, SMARCB1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.501C>G	p.Cys167Trp	missense_variant, splice_region_variant	5/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.555C>G	p.His185Gln	missense_variant, splice_region_variant	5/9
SMARCB1	NM_001317946.2	c.528C>G	p.His176Gln	missense_variant, splice_region_variant	5/9
SMARCB1	NM_001007468.3	c.474C>G	p.Cys158Trp	missense_variant, splice_region_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.501C>G	p.Cys167Trp	missense_variant, splice_region_variant	5/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461826 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727216

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2021

This sequence change replaces cysteine with tryptophan at codon 167 of the SMARCB1 protein (p.Cys167Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The p.C167W variant (also known as c.501C>G), located in coding exon 5 of the SMARCB1 gene, results from a C to G substitution at nucleotide position 501. This variant impacts the first base pair of coding exon 5. The cysteine at codon 167 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.83
Sift	Benign	0.042	D;.
Sift4G	Uncertain	0.014	D;.
Polyphen		0.0010	.;B
Vest4		0.83
MutPred		0.71		.;Gain of MoRF binding (P = 0.0359);
MVP		0.97
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.60
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: rs779221331; hg19: chr22-24145482;