rs35502837

chr22-23801386-C-Achr22-23801386-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003073.5(SMARCB1):c.500+305C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 667,950 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (39 hom., cov: 32)
  • Exomes 𝑓: 0.027 (249 hom.)
• Consequence: SMARCB1 NM_003073.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -1.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-23801386-C-A is Benign according to our data. Variant chr22-23801386-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 133393.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0209 (3181/152324) while in subpopulation NFE AF= 0.0294 (2002/68024). AF 95% confidence interval is 0.0284. There are 39 homozygotes in gnomad4. There are 1613 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.500+305C>A		intron_variant		ENST00000644036.2
SMARCB1	NM_001007468.3	c.473+305C>A		intron_variant
SMARCB1	NM_001317946.2	c.527+251C>A		intron_variant
SMARCB1	NM_001362877.2	c.554+251C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.500+305C>A		intron_variant			NM_003073.5	A1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3182 AN: 152206 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0231 AC: 2963 AN: 128418 Hom.: 55 AF XY: 0.0244 AC XY: 1717 AN XY: 70236

Gnomad AFR exome AF: 0.00473

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0374

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0284

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0268 AC: 13835 AN: 515626 Hom.: 249 Cov.: 0 AF XY: 0.0275 AC XY: 7691 AN XY: 279670

Gnomad4 AFR exome AF: 0.00540

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0260

GnomAD4 genome AF: 0.0209 AC: 3181 AN: 152324 Hom.: 39 Cov.: 32 AF XY: 0.0217 AC XY: 1613 AN XY: 74484

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.0228 Hom.: 18

Bravo AF: 0.0183

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

This variant is associated with the following publications: (PMID: 24728327) -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.28
Dann	Benign	0.56

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: rs35502837; hg19: chr22-24143573; COSMIC: COSV54093735; COSMIC: COSV54093735;