rs1060503019

Positions:

• chr22-23816854-C-G
• chr22-23816854-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003073.5(SMARCB1):​c.713C>G​(p.Ala238Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A238T) 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: 7.86

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.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.713C>G	p.Ala238Gly	missense_variant	6/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.767C>G	p.Ala256Gly	missense_variant	6/9
SMARCB1	NM_001317946.2	c.740C>G	p.Ala247Gly	missense_variant	6/9
SMARCB1	NM_001007468.3	c.686C>G	p.Ala229Gly	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.713C>G	p.Ala238Gly	missense_variant	6/9		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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.1	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;.;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;.;D;.
Sift4G	Uncertain	0.010	D;.;D;.
Polyphen		0.30, 0.23	.;B;B;.
Vest4		0.68
MutPred		0.64		.;.;Loss of catalytic residue at A247 (P = 0.0815);.;
MVP		0.72
MPC		2.0
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.77

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: chr22-24159041;