rs2229354

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003073.5(SMARCB1):c.897G>A(p.Ser299Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,008 control chromosomes in the GnomAD database, including 10,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S299S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 880 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10101 hom. )

Consequence

SMARCB1
NM_003073.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.33

Publications

37 publications found

Variant links:

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

SMARCB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 22-23825326-G-A is Benign according to our data. Variant chr22-23825326-G-A is described in ClinVar as Benign. ClinVar VariationId is 126368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5 link	c.897G>A	p.Ser299Ser	synonymous_variant	Exon 7 of 9	ENST00000644036.2	NP_003064.2	Q12824-1
SMARCB1	NM_001362877.2 link	c.951G>A	p.Ser317Ser	synonymous_variant	Exon 7 of 9		NP_001349806.1
SMARCB1	NM_001317946.2 link	c.924G>A	p.Ser308Ser	synonymous_variant	Exon 7 of 9		NP_001304875.1	G5E975Q9H836
SMARCB1	NM_001007468.3 link	c.870G>A	p.Ser290Ser	synonymous_variant	Exon 7 of 9		NP_001007469.1	Q12824-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 link	c.897G>A	p.Ser299Ser	synonymous_variant	Exon 7 of 9		NM_003073.5	ENSP00000494049.2		Q12824-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16051

AN:

152170

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.0884

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.0750

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.112

AC:

28247

AN:

251442

AF XY:

0.116

show subpopulations

Gnomad AFR exome

AF:

0.0866

Gnomad AMR exome

AF:

0.0770

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.0777

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.114

AC:

166761

AN:

1461720

Hom.:

10101

Cov.:

AF XY:

0.116

AC XY:

84346

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0854

AC:

2859

AN:

33478

American (AMR)

AF:

0.0787

AC:

3520

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

2788

AN:

26134

East Asian (EAS)

AF:

0.0460

AC:

1826

AN:

39698

South Asian (SAS)

AF:

0.176

AC:

15171

AN:

86254

European-Finnish (FIN)

AF:

0.128

AC:

6850

AN:

53418

Middle Eastern (MID)

AF:

0.154

AC:

886

AN:

5768

European-Non Finnish (NFE)

AF:

0.113

AC:

125780

AN:

1111866

Other (OTH)

AF:

0.117

AC:

7081

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

8397

16794

25192

33589

41986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4528

9056

13584

18112

22640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.105

AC:

16048

AN:

152288

Hom.:

880

Cov.:

AF XY:

0.106

AC XY:

7884

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0858

AC:

3567

AN:

41554

American (AMR)

AF:

0.0884

AC:

1352

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

350

AN:

3472

East Asian (EAS)

AF:

0.0747

AC:

387

AN:

5178

South Asian (SAS)

AF:

0.169

AC:

817

AN:

4824

European-Finnish (FIN)

AF:

0.130

AC:

1379

AN:

10628

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7799

AN:

68012

Other (OTH)

AF:

0.111

AC:

234

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

742

1484

2227

2969

3711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.103

Hom.:

795

Bravo

AF:

0.0997

Asia WGS

AF:

0.106

AC:

367

AN:

3478

EpiCase

AF:

0.114

EpiControl

AF:

0.115

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 29, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SMARCB1 c.897G>A (p.Ser299Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant along with 3/5 splice tools predicting the variant not to have an impact on normal splicing. This variant was found in 13842/121354 control chromosomes (893 homozygotes), predominantly observed in the South Asian (284 homozygotes) subpopulation at a frequency of 0.1737945 (2869/16508). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic SMARCB1 variant (0.0000001), suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. One clinical diagnostic laboratory classified this variant as Benign. Taken together, this variant is classified as Benign. -

Rhabdoid tumor predisposition syndrome 1

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

SMARCB1-related schwannomatosis

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 19, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.13

(source)

DANN

Benign

0.50

PhyloP100

-3.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over