rs28997582

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BA1

The NM_001387283.1(SMARCA4):c.4053C>T(p.Asp1351Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,611,880 control chromosomes in the GnomAD database, including 3,655 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 240 hom., cov: 33)

Exomes 𝑓: 0.065 ( 3415 hom. )

Consequence

SMARCA4
NM_001387283.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.33

Publications

20 publications found

Variant links:

COSMIC-nc: COSV60798637

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP6

Variant 19-11035015-C-T is Benign according to our data. Variant chr19-11035015-C-T is described in ClinVar as Benign. ClinVar VariationId is 126362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4053C>T	p.Asp1351Asp	synonymous_variant	Exon 29 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4053C>T	p.Asp1351Asp	synonymous_variant	Exon 29 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.4053C>T	p.Asp1351Asp	synonymous_variant	Exon 29 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.4053C>T	p.Asp1351Asp	synonymous_variant	Exon 29 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.3954C>T	p.Asp1318Asp	synonymous_variant	Exon 28 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.3954C>T	p.Asp1318Asp	synonymous_variant	Exon 29 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.3954C>T	p.Asp1318Asp	synonymous_variant	Exon 28 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.3954C>T	p.Asp1318Asp	synonymous_variant	Exon 28 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.3954C>T	p.Asp1318Asp	synonymous_variant	Exon 29 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.3465C>T	p.Asp1155Asp	synonymous_variant	Exon 26 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.2697C>T	p.Asp899Asp	synonymous_variant	Exon 22 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.2679C>T	p.Asp893Asp	synonymous_variant	Exon 21 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.2538C>T	p.Asp846Asp	synonymous_variant	Exon 21 of 27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.2406C>T	p.Asp802Asp	synonymous_variant	Exon 20 of 25			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 link	c.210C>T	p.Asp70Asp	synonymous_variant	Exon 3 of 8	3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

AF:

0.0483

AC:

7347

AN:

152126

Hom.:

240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0701

Gnomad EAS

AF:

0.0339

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0922

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0626

Gnomad OTH

AF:

0.0565

GnomAD2 exomes

AF:

0.0608

AC:

14942

AN:

245954

AF XY:

0.0646

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.0297

Gnomad ASJ exome

AF:

0.0672

Gnomad EAS exome

AF:

0.0340

Gnomad FIN exome

AF:

0.0869

Gnomad NFE exome

AF:

0.0643

Gnomad OTH exome

AF:

0.0685

GnomAD4 exome

AF:

0.0647

AC:

94438

AN:

1459636

Hom.:

3415

Cov.:

AF XY:

0.0660

AC XY:

47934

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.0110

AC:

369

AN:

33452

American (AMR)

AF:

0.0318

AC:

1419

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.0667

AC:

1741

AN:

26086

East Asian (EAS)

AF:

0.0262

AC:

1041

AN:

39664

South Asian (SAS)

AF:

0.102

AC:

8765

AN:

86028

European-Finnish (FIN)

AF:

0.0882

AC:

4635

AN:

52522

Middle Eastern (MID)

AF:

0.0666

AC:

378

AN:

5674

European-Non Finnish (NFE)

AF:

0.0650

AC:

72267

AN:

1111336

Other (OTH)

AF:

0.0634

AC:

3823

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5433

10865

16298

21730

27163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2730

5460

8190

10920

13650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0483

AC:

7355

AN:

152244

Hom.:

240

Cov.:

AF XY:

0.0504

AC XY:

3753

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0129

AC:

537

AN:

41570

American (AMR)

AF:

0.0335

AC:

513

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0701

AC:

243

AN:

3468

East Asian (EAS)

AF:

0.0342

AC:

176

AN:

5152

South Asian (SAS)

AF:

0.104

AC:

499

AN:

4818

European-Finnish (FIN)

AF:

0.0922

AC:

977

AN:

10600

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0626

AC:

4259

AN:

68010

Other (OTH)

AF:

0.0582

AC:

123

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

358

716

1073

1431

1789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0573

Hom.:

407

Bravo

AF:

0.0418

Asia WGS

AF:

0.0840

AC:

292

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Intellectual disability, autosomal dominant 16

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Coffin-Siris syndrome

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. -

Hereditary cancer-predisposing syndrome

Benign:1

May 20, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.73

CADD

Benign

0.045

(source)

DANN

Benign

0.82

PhyloP100

-2.3

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over