rs797045989

Variant names:

• chr22-23833672-A-G
• rs797045989
• NM_003073.5:c.1087A>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003073.5(SMARCB1):​c.1087A>G​(p.Lys363Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K363N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.03

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 22) in uniprot entity SNF5_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23833674-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 22-23833672-A-G is Pathogenic according to our data. Variant chr22-23833672-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.1087A>G	p.Lys363Glu	missense_variant	Exon 8 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.1141A>G	p.Lys381Glu	missense_variant	Exon 8 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.1114A>G	p.Lys372Glu	missense_variant	Exon 8 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.1060A>G	p.Lys354Glu	missense_variant	Exon 8 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1087A>G	p.Lys363Glu	missense_variant	Exon 8 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:2

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar VCV000212263.2, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.874, 3Cnet: 0.943, PP3). Patient's phenotype is considered compatible with Coffin-Siris syndrome 3 (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

May 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.5	.;M;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D;.;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Uncertain	0.056	T;.;T;.
Polyphen		0.88, 0.92	.;P;P;.
Vest4		0.80
MutPred		0.67		.;.;Loss of methylation at K372 (P = 0.0037);.;
MVP		0.96
MPC		2.8
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.99

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: rs797045989; hg19: chr22-24175859;