19-10995924-C-T

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.1594-289C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 474,168 control chromosomes in the GnomAD database, including 27,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 7878 hom., cov: 32)

Exomes 𝑓: 0.34 ( 19540 hom. )

Consequence

SMARCA4
NM_001387283.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.356

Publications

11 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 (MetaRNN=3.463626E-4).

BP6

Variant 19-10995924-C-T is Benign according to our data. Variant chr19-10995924-C-T is described in ClinVar as Benign. ClinVar VariationId is 1237367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1594-289C>T		intron_variant	Intron 9 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1594-289C>T		intron_variant	Intron 9 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.1594-289C>T	intron_variant	Intron 9 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.1594-289C>T	intron_variant	Intron 9 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.1594-289C>T	intron_variant	Intron 9 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.1594-289C>T	intron_variant	Intron 10 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.1594-289C>T	intron_variant	Intron 9 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.1594-289C>T	intron_variant	Intron 9 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.1594-289C>T	intron_variant	Intron 10 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.1006-289C>T	intron_variant	Intron 6 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.238-289C>T	intron_variant	Intron 2 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.322-289C>T	intron_variant	Intron 2 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.82-289C>T	intron_variant	Intron 1 of 26			ENSP00000495355.1

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48260

AN:

151740

Hom.:

7860

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.350

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.369

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.316

GnomAD2 exomes

AF:

0.306

AC:

19552

AN:

63824

AF XY:

0.313

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.325

Gnomad EAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.346

Gnomad NFE exome

AF:

0.352

Gnomad OTH exome

AF:

0.331

GnomAD4 exome

AF:

0.338

AC:

109085

AN:

322310

Hom.:

19540

Cov.:

AF XY:

0.346

AC XY:

60289

AN XY:

174114

show subpopulations

African (AFR)

AF:

0.277

AC:

2627

AN:

9496

American (AMR)

AF:

0.203

AC:

3516

AN:

17282

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

3195

AN:

9580

East Asian (EAS)

AF:

0.221

AC:

4056

AN:

18344

South Asian (SAS)

AF:

0.429

AC:

19849

AN:

46250

European-Finnish (FIN)

AF:

0.361

AC:

5500

AN:

15252

Middle Eastern (MID)

AF:

0.375

AC:

1109

AN:

2960

European-Non Finnish (NFE)

AF:

0.342

AC:

63382

AN:

185510

Other (OTH)

AF:

0.332

AC:

5851

AN:

17636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3982

7964

11946

15928

19910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.318

AC:

48315

AN:

151858

Hom.:

7878

Cov.:

AF XY:

0.320

AC XY:

23731

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.282

AC:

11669

AN:

41410

American (AMR)

AF:

0.236

AC:

3608

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

1215

AN:

3468

East Asian (EAS)

AF:

0.245

AC:

1264

AN:

5164

South Asian (SAS)

AF:

0.412

AC:

1982

AN:

4808

European-Finnish (FIN)

AF:

0.369

AC:

3893

AN:

10546

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.348

AC:

23617

AN:

67886

Other (OTH)

AF:

0.317

AC:

668

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1697

3394

5090

6787

8484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<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:

0.322

Hom.:

1104

Bravo

AF:

0.304

TwinsUK

AF:

0.359

AC:

1333

ALSPAC

AF:

0.360

AC:

1388

ExAC

AF:

0.169

AC:

6322

Asia WGS

AF:

0.331

AC:

1153

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

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.91

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.94

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.10

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00070

LIST_S2

Benign

0.75

MetaRNN

Benign

0.00035

MetaSVM

Benign

-1.0

PhyloP100

-0.36

Sift4G

Uncertain

0.0020

Vest4

0.14

ClinPred

0.0045

GERP RS

-5.0

PromoterAI

-0.0060

Neutral

(source)

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