rs1205121674

chr22-23833659-C-Achr22-23833659-C-Gchr22-23833659-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_003073.5(SMARCB1):c.1074C>A(p.Asp358Glu) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D358D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMARCB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.39560285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.1074C>A	p.Asp358Glu	missense_variant	8/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.1128C>A	p.Asp376Glu	missense_variant	8/9
SMARCB1	NM_001317946.2	c.1101C>A	p.Asp367Glu	missense_variant	8/9
SMARCB1	NM_001007468.3	c.1047C>A	p.Asp349Glu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1074C>A	p.Asp358Glu	missense_variant	8/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	2.0
Dann	Benign	0.89
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.13	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	N;.;D;.
REVEL	Uncertain	0.47
Sift	Benign	0.28	T;.;T;.
Sift4G	Uncertain	0.010	D;.;D;.
Polyphen		0.98, 0.95	.;D;P;.
Vest4		0.61
MutPred		0.54		.;.;Gain of disorder (P = 0.1298);.;
MVP		0.72
MPC		2.3
ClinPred		0.92	D
GERP RS		-6.9
Varity_R		0.23
gMVP		0.91

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: chr22-24175846;