rs1555881567

Positions:

• chr22-23833655-C-G
• chr22-23833655-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_003073.5(SMARCB1):​c.1070C>G​(p.Thr357Arg) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T357I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.66

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr22-23833655-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 580796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SMARCB1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 22-23833655-C-G is Pathogenic according to our data. Variant chr22-23833655-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559897.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.1070C>G	p.Thr357Arg	missense_variant	8/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.1124C>G	p.Thr375Arg	missense_variant	8/9
SMARCB1	NM_001317946.2	c.1097C>G	p.Thr366Arg	missense_variant	8/9
SMARCB1	NM_001007468.3	c.1043C>G	p.Thr348Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1070C>G	p.Thr357Arg	missense_variant	8/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jun 21, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SMARCB1 related disorder (ClinVar ID: VCV000559897). A different missense change at the same codon (p.Thr357Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000580796). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2019

The p.T357R variant (also known as c.1070C>G), located in coding exon 8 of the SMARCB1 gene, results from a C to G substitution at nucleotide position 1070. The threonine at codon 357 is replaced by arginine, an amino acid with similar 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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.4	D;.;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.025	D;.;D;.
Sift4G	Uncertain	0.0020	D;.;D;.
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.91
MutPred		0.72		.;.;Loss of phosphorylation at T366 (P = 0.0398);.;
MVP		0.90
MPC		2.7
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.99

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: rs1555881567; hg19: chr22-24175842;