Genetic Variant SMARCB1:c.-117C>T (chr22-23787053-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003073.5(SMARCB1):c.-117C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 686,180 control chromosomes in the GnomAD database, including 4,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 681 hom., cov: 33)

Exomes 𝑓: 0.11 ( 3390 hom. )

Consequence

SMARCB1
NM_003073.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.40

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 22-23787053-C-T is Benign according to our data. Variant chr22-23787053-C-T is described in ClinVar as [Benign]. Clinvar id is 340908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5 link	c.-117C>T	5_prime_UTR_variant	Exon 1 of 9	ENST00000644036.2	NP_003064.2	Q12824-1
SMARCB1	NM_001362877.2 link	c.-117C>T	5_prime_UTR_variant	Exon 1 of 9		NP_001349806.1
SMARCB1	NM_001317946.2 link	c.-117C>T	5_prime_UTR_variant	Exon 1 of 9		NP_001304875.1	G5E975Q9H836
SMARCB1	NM_001007468.3 link	c.-117C>T	5_prime_UTR_variant	Exon 1 of 9		NP_001007469.1	Q12824-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036 link	c.-117C>T		5_prime_UTR_variant	Exon 1 of 9		NM_003073.5	ENSP00000494049.2		Q12824-1

Frequencies

GnomAD3 genomes

AF:

0.0821

AC:

12498

AN:

152142

Hom.:

682

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0209

Gnomad AMI

AF:

0.0954

Gnomad AMR

AF:

0.0870

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.0818

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.0833

GnomAD4 exome

AF:

0.107

AC:

57227

AN:

533932

Hom.:

3390

Cov.:

AF XY:

0.110

AC XY:

31589

AN XY:

288084

show subpopulations

Gnomad4 AFR exome

AF:

0.0210

Gnomad4 AMR exome

AF:

0.0960

Gnomad4 ASJ exome

AF:

0.113

Gnomad4 EAS exome

AF:

0.148

Gnomad4 SAS exome

AF:

0.140

Gnomad4 FIN exome

AF:

0.0810

Gnomad4 NFE exome

AF:

0.106

Gnomad4 OTH exome

AF:

0.0963

GnomAD4 genome

AF:

0.0820

AC:

12482

AN:

152248

Hom.:

681

Cov.:

AF XY:

0.0828

AC XY:

6167

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0208

Gnomad4 AMR

AF:

0.0868

Gnomad4 ASJ

AF:

0.115

Gnomad4 EAS

AF:

0.150

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.0818

Gnomad4 NFE

AF:

0.107

Gnomad4 OTH

AF:

0.0819

Alfa

AF:

0.0883

Hom.:

Bravo

AF:

0.0781

Asia WGS

AF:

0.127

AC:

440

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

GeneDx

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

- -

Rhabdoid tumor predisposition syndrome 1

Benign:1

Jan 13, 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:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.8

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over