rs754350320

Positions:

• chr22-23793684-C-A
• chr22-23793684-C-G
• chr22-23793684-C-T

Variant summary

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

The NM_003073.5(SMARCB1):​c.358C>A​(p.Leu120Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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.

• 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.358C>A	p.Leu120Ile	missense_variant	3/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.358C>A	p.Leu120Ile	missense_variant	3/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.331C>A	p.Leu111Ile	missense_variant	3/9		NP_001304875.1
SMARCB1	NM_001007468.3	c.331C>A	p.Leu111Ile	missense_variant	3/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.358C>A	p.Leu120Ile	missense_variant	3/9		NM_003073.5	ENSP00000494049	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.28	.;T;T;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.44	.;.;.;.;T;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.90	.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.37	N;.;N;N;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.24	T;.;T;T;.;T
Sift4G	Benign	0.55	T;.;T;T;.;T
Polyphen		0.41, 0.88, 0.98	.;B;P;.;.;D
Vest4		0.43
MutPred		0.14		Loss of ubiquitination at K115 (P = 0.0648);.;Loss of ubiquitination at K115 (P = 0.0648);.;Loss of ubiquitination at K115 (P = 0.0648);.;
MVP		0.73
MPC		1.4
ClinPred		0.79	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.36

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: chr22-24135871;