Genetic Variant SMARCB1:c.500+305C>A (chr22-23801386-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -1.06

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=-0.88).

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_multiple_submitters_no_conflicts, 2 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. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5 link	c.500+305C>A	intron_variant	Intron 4 of 8	ENST00000644036.2	NP_003064.2	Q12824-1
SMARCB1	NM_001362877.2 link	c.554+251C>A	intron_variant	Intron 4 of 8		NP_001349806.1
SMARCB1	NM_001317946.2 link	c.527+251C>A	intron_variant	Intron 4 of 8		NP_001304875.1	G5E975Q9H836
SMARCB1	NM_001007468.3 link	c.473+305C>A	intron_variant	Intron 4 of 8		NP_001007469.1	Q12824-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 link	c.500+305C>A		intron_variant	Intron 4 of 8		NM_003073.5	ENSP00000494049.2		Q12824-1

Frequencies

GnomAD3 genomes

AF:

0.0209

AC:

3182

AN:

152206

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0244

AC XY:

1717

AN XY:

70236

show subpopulations

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.:

AF XY:

0.0275

AC XY:

7691

AN XY:

279670

show subpopulations

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.:

Cov.:

AF XY:

0.0217

AC XY:

1613

AN XY:

74484

show subpopulations

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.:

Bravo

AF:

0.0183

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

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

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