rs2229354

chr22-23825326-G-Achr22-23825326-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003073.5(SMARCB1):c.897G>A(p.Ser299=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.33

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 -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 id is 126368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23825326-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.897G>A	p.Ser299=	synonymous_variant	7/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.951G>A	p.Ser317=	synonymous_variant	7/9
SMARCB1	NM_001317946.2	c.924G>A	p.Ser308=	synonymous_variant	7/9
SMARCB1	NM_001007468.3	c.870G>A	p.Ser290=	synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.897G>A	p.Ser299=	synonymous_variant	7/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16051 AN: 152170 Hom.: 880 Cov.: 33

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

GnomAD3 exomes AF: 0.112 AC: 28247 AN: 251442 Hom.: 1764 AF XY: 0.116 AC XY: 15827 AN XY: 135904

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 SAS exome AF: 0.176

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.: 32 AF XY: 0.116 AC XY: 84346 AN XY: 727164

Gnomad4 AFR exome AF: 0.0854

Gnomad4 AMR exome AF: 0.0787

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.0460

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.105 AC: 16048 AN: 152288 Hom.: 880 Cov.: 33 AF XY: 0.106 AC XY: 7884 AN XY: 74464

Gnomad4 AFR AF: 0.0858

Gnomad4 AMR AF: 0.0884

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.0747

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.111

Alfa AF: 0.101 Hom.: 592

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Rhabdoid tumor predisposition syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	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. -

Schwannomatosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2016

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
Dann	Benign	0.50

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: rs2229354; hg19: chr22-24167513; COSMIC: COSV54093776;