rs12232780

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001387283.1(SMARCA4):c.2617-321G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 440,446 control chromosomes in the GnomAD database, including 18,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4941 hom., cov: 33)

Exomes 𝑓: 0.30 ( 13584 hom. )

Consequence

SMARCA4
NM_001387283.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.325

Publications

25 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 19-11021404-G-A is Benign according to our data. Variant chr19-11021404-G-A is described in ClinVar as [Benign]. Clinvar id is 1249450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.2617-321G>A		intron_variant	Intron 18 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.2617-321G>A		intron_variant	Intron 18 of 34	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.2617-321G>A	intron_variant	Intron 18 of 35		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.2617-321G>A	intron_variant	Intron 18 of 34	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.2617-321G>A	intron_variant	Intron 18 of 34			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.2617-321G>A	intron_variant	Intron 19 of 34	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.2617-321G>A	intron_variant	Intron 18 of 33			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.2617-321G>A	intron_variant	Intron 18 of 33			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.2617-321G>A	intron_variant	Intron 19 of 34	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.2029-321G>A	intron_variant	Intron 15 of 31			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.1261-321G>A	intron_variant	Intron 11 of 27			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.1342-321G>A	intron_variant	Intron 11 of 26			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.1102-321G>A	intron_variant	Intron 10 of 26			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.970-321G>A	intron_variant	Intron 9 of 24			ENSP00000494159.1	A0A2R8Y526

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

36013

AN:

152066

Hom.:

4943

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0918

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.218

Gnomad SAS

AF:

0.345

Gnomad FIN

AF:

0.346

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.242

GnomAD4 exome

AF:

0.297

AC:

85670

AN:

288262

Hom.:

13584

Cov.:

AF XY:

0.305

AC XY:

46840

AN XY:

153512

show subpopulations

African (AFR)

AF:

0.0840

AC:

738

AN:

8784

American (AMR)

AF:

0.179

AC:

3060

AN:

17064

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

2789

AN:

8730

East Asian (EAS)

AF:

0.209

AC:

3305

AN:

15850

South Asian (SAS)

AF:

0.365

AC:

17109

AN:

46850

European-Finnish (FIN)

AF:

0.340

AC:

4499

AN:

13224

Middle Eastern (MID)

AF:

0.343

AC:

803

AN:

2344

European-Non Finnish (NFE)

AF:

0.306

AC:

48810

AN:

159624

Other (OTH)

AF:

0.289

AC:

4557

AN:

15792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

3165

6331

9496

12662

15827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.237

AC:

36013

AN:

152184

Hom.:

4941

Cov.:

AF XY:

0.241

AC XY:

17900

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0916

AC:

3807

AN:

41546

American (AMR)

AF:

0.194

AC:

2965

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1134

AN:

3470

East Asian (EAS)

AF:

0.218

AC:

1129

AN:

5178

South Asian (SAS)

AF:

0.345

AC:

1664

AN:

4826

European-Finnish (FIN)

AF:

0.346

AC:

3667

AN:

10584

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20786

AN:

67966

Other (OTH)

AF:

0.244

AC:

516

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1387

2774

4161

5548

6935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.272

Hom.:

4152

Bravo

AF:

0.218

Asia WGS

AF:

0.266

AC:

928

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.16

(source)

DANN

Benign

0.38

PhyloP100

-0.33

PromoterAI

0.024

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs12232780

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