chr22-23803396-G-A

Variant names:

• chr22-23803396-G-A
• rs1555877287
• NM_003073.5:c.602G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003073.5(SMARCB1):​c.602G>A​(p.Arg201Gln) 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 (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.96
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schwannomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 22-23803396-G-A is Pathogenic according to our data. Variant chr22-23803396-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438304.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003073.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	NM_003073.5	MANE Select	c.602G>A	p.Arg201Gln	missense	Exon 5 of 9	NP_003064.2
	SMARCB1	NM_001362877.2		c.656G>A	p.Arg219Gln	missense	Exon 5 of 9	NP_001349806.1
	SMARCB1	NM_001317946.2		c.629G>A	p.Arg210Gln	missense	Exon 5 of 9	NP_001304875.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	ENST00000644036.2	MANE Select	c.602G>A	p.Arg201Gln	missense	Exon 5 of 9	ENSP00000494049.2
	SMARCB1	ENST00000407422.8	TSL:1	c.575G>A	p.Arg192Gln	missense	Exon 5 of 9	ENSP00000383984.3
	SMARCB1	ENST00000263121.12	TSL:1	c.464G>A	p.Arg155Gln	missense	Exon 4 of 8	ENSP00000263121.8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:1

Nov 01, 2016

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.82
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.58	P
Vest4		0.90
MutPred		0.83		Gain of ubiquitination at K208 (P = 0.0882)
MVP		0.93
MPC		2.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.90
Mutation Taster		=25/75	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555877287; hg19: chr22-24145583; COSMIC: COSV54093015; COSMIC: COSV54093015;