rs7935

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001387283.1(SMARCA4):c.1524T>C(p.His508His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,613,226 control chromosomes in the GnomAD database, including 100,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8201 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92385 hom. )

Consequence

SMARCA4
NM_001387283.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.80

Publications

42 publications found

Variant links:

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 19-10994932-T-C is Benign according to our data. Variant chr19-10994932-T-C is described in ClinVar as Benign. ClinVar VariationId is 126359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1524T>C	p.His508His	synonymous_variant	Exon 9 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1524T>C	p.His508His	synonymous_variant	Exon 9 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.1524T>C	p.His508His	synonymous_variant	Exon 9 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.1524T>C	p.His508His	synonymous_variant	Exon 9 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.1524T>C	p.His508His	synonymous_variant	Exon 9 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.1524T>C	p.His508His	synonymous_variant	Exon 10 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.1524T>C	p.His508His	synonymous_variant	Exon 9 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.1524T>C	p.His508His	synonymous_variant	Exon 9 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.1524T>C	p.His508His	synonymous_variant	Exon 10 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.936T>C	p.His312His	synonymous_variant	Exon 6 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.168T>C	p.His56His	synonymous_variant	Exon 2 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.252T>C	p.His84His	synonymous_variant	Exon 2 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.12T>C	p.His4His	synonymous_variant	Exon 1 of 27			ENSP00000495355.1	A0A2R8Y6N0

Frequencies

GnomAD3 genomes

AF:

0.325

AC:

49334

AN:

151958

Hom.:

8181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.320

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.350

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.349

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.328

AC:

82139

AN:

250764

AF XY:

0.339

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.340

Gnomad EAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.359

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.346

GnomAD4 exome

AF:

0.352

AC:

514614

AN:

1461150

Hom.:

92385

Cov.:

AF XY:

0.355

AC XY:

258355

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.305

AC:

10196

AN:

33466

American (AMR)

AF:

0.197

AC:

8799

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

8988

AN:

26134

East Asian (EAS)

AF:

0.226

AC:

8980

AN:

39696

South Asian (SAS)

AF:

0.433

AC:

37300

AN:

86230

European-Finnish (FIN)

AF:

0.361

AC:

19260

AN:

53388

Middle Eastern (MID)

AF:

0.386

AC:

2226

AN:

5768

European-Non Finnish (NFE)

AF:

0.358

AC:

398035

AN:

1111428

Other (OTH)

AF:

0.345

AC:

20830

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18653

37306

55960

74613

93266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12722

25444

38166

50888

63610

<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:

0.325

AC:

49391

AN:

152076

Hom.:

8201

Cov.:

AF XY:

0.326

AC XY:

24220

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.304

AC:

12612

AN:

41482

American (AMR)

AF:

0.238

AC:

3639

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

1216

AN:

3472

East Asian (EAS)

AF:

0.244

AC:

1254

AN:

5148

South Asian (SAS)

AF:

0.413

AC:

1990

AN:

4822

European-Finnish (FIN)

AF:

0.368

AC:

3895

AN:

10582

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.349

AC:

23708

AN:

67988

Other (OTH)

AF:

0.321

AC:

677

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1749

3497

5246

6994

8743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.340

Hom.:

40294

Bravo

AF:

0.312

Asia WGS

AF:

0.333

AC:

1158

AN:

3478

EpiCase

AF:

0.362

EpiControl

AF:

0.353

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 30, 2015

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. -

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 19, 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

-0.57

CADD

Benign

0.065

(source)

DANN

Benign

0.39

PhyloP100

-1.8

PromoterAI

0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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