22-23787171-T-C

Position:

• chr22-23787171-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003073.5(SMARCB1):​c.2T>C​(p.Met1?) variant causes a start lost 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.2T>C	p.Met1?	start_lost	1/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.2T>C	p.Met1?	start_lost	1/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.2T>C	p.Met1?	start_lost	1/9		NP_001304875.1
SMARCB1	NM_001007468.3	c.2T>C	p.Met1?	start_lost	1/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.2T>C	p.Met1?	start_lost	1/9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the SMARCB1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 1 amino acid from the initiation site, which may result in N-terminal truncation of unknown functional significance. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.27	.;T;T;.;.;T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.0083
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;.;.;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
PROVEAN	Benign	-0.24	N;.;N;N;N;N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.;D;D;D;D
Sift4G	Uncertain	0.012	D;.;D;D;D;D
Polyphen		0.0, 0.0010, 0.72	.;B;B;.;.;P
Vest4		0.76
MutPred		0.83		Gain of glycosylation at M1 (P = 0.0054);Gain of glycosylation at M1 (P = 0.0054);Gain of glycosylation at M1 (P = 0.0054);Gain of glycosylation at M1 (P = 0.0054);Gain of glycosylation at M1 (P = 0.0054);Gain of glycosylation at M1 (P = 0.0054);
MVP		0.84
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24129358;