22-23787053-C-T

Position:

• chr22-23787053-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.40

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 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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.-117C>T		5_prime_UTR_variant	1/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001007468.3	c.-117C>T		5_prime_UTR_variant	1/9		NP_001007469.1
SMARCB1	NM_001317946.2	c.-117C>T		5_prime_UTR_variant	1/9		NP_001304875.1
SMARCB1	NM_001362877.2	c.-117C>T		5_prime_UTR_variant	1/9		NP_001349806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.-117C>T		5_prime_UTR_variant	1/9		NM_003073.5	ENSP00000494049	A1

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 12498 AN: 152142 Hom.: 682 Cov.: 33

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.: 7 AF XY: 0.110 AC XY: 31589 AN XY: 288084

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.: 33 AF XY: 0.0828 AC XY: 6167 AN XY: 74448

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.: 89

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rhabdoid tumor predisposition syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Schwannomatosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Other links and lift over

dbSNP: rs11090285; hg19: chr22-24129240;