22-23803379-C-G

Position:

• chr22-23803379-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003073.5(SMARCB1):​c.585C>G​(p.Ile195Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.40

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]

SMARCB1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCB1. . Gene score misZ 3.6016 (greater than the threshold 3.09). Trascript score misZ 4.8554 (greater than threshold 3.09). GenCC has associacion of gene with schwannomatosis 1, familial multiple meningioma, rhabdoid tumor predisposition syndrome 1, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 15, familial rhabdoid tumor, schwannomatosis, Coffin-Siris syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.585C>G	p.Ile195Met	missense_variant	5/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.639C>G	p.Ile213Met	missense_variant	5/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.612C>G	p.Ile204Met	missense_variant	5/9		NP_001304875.1
SMARCB1	NM_001007468.3	c.558C>G	p.Ile186Met	missense_variant	5/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.585C>G	p.Ile195Met	missense_variant	5/9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2021

This sequence change replaces isoleucine with methionine at codon 195 of the SMARCB1 protein (p.Ile195Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). 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. 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. This variant has not been reported in the literature in individuals with SMARCB1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	2.6
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;T;T;.;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Pathogenic	0.99	.;.;.;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.0	.;M;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.3	N;.;N;.;.;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.023	D;.;D;.;.;D
Sift4G	Uncertain	0.021	D;.;D;.;.;D
Polyphen		0.50, 0.71, 0.86	.;P;P;.;.;P
Vest4		0.74
MutPred		0.36		.;.;Loss of catalytic residue at L209 (P = 0.0271);.;.;.;
MVP		0.86
MPC		1.6
ClinPred		0.98	D
GERP RS		-6.6
Varity_R		0.73
gMVP		0.69

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: rs757546528; hg19: chr22-24145566;