19-11003321-G-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.1944-19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 1,611,630 control chromosomes in the GnomAD database, including 3,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.061 ( 317 hom., cov: 32)

Exomes 𝑓: 0.067 ( 3673 hom. )

Consequence

SMARCA4
NM_001387283.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0440

Publications

13 publications found

Variant links:

COSMIC-nc: COSV60798617

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=-0.84).

BP6

Variant 19-11003321-G-T is Benign according to our data. Variant chr19-11003321-G-T is described in ClinVar as Benign. ClinVar VariationId is 257530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1944-19G>T		intron_variant	Intron 12 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1944-19G>T		intron_variant	Intron 12 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.1944-19G>T	intron_variant	Intron 12 of 35		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.1944-19G>T	intron_variant	Intron 12 of 34	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.1944-19G>T	intron_variant	Intron 12 of 34			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.1944-19G>T	intron_variant	Intron 13 of 34	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.1944-19G>T	intron_variant	Intron 12 of 33			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.1944-19G>T	intron_variant	Intron 12 of 33			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.1944-19G>T	intron_variant	Intron 13 of 34	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.1356-19G>T	intron_variant	Intron 9 of 31			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.588-19G>T	intron_variant	Intron 5 of 27			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.669-19G>T	intron_variant	Intron 5 of 26			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.429-19G>T	intron_variant	Intron 4 of 26			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.297-19G>T	intron_variant	Intron 3 of 24			ENSP00000494159.1	A0A2R8Y526

Frequencies

GnomAD3 genomes

AF:

0.0612

AC:

9307

AN:

152144

Hom.:

318

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0532

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0374

Gnomad ASJ

AF:

0.0779

Gnomad EAS

AF:

0.0338

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0933

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0641

Gnomad OTH

AF:

0.0694

GnomAD2 exomes

AF:

0.0657

AC:

16526

AN:

251468

AF XY:

0.0695

show subpopulations

Gnomad AFR exome

AF:

0.0520

Gnomad AMR exome

AF:

0.0309

Gnomad ASJ exome

AF:

0.0702

Gnomad EAS exome

AF:

0.0335

Gnomad FIN exome

AF:

0.0880

Gnomad NFE exome

AF:

0.0660

Gnomad OTH exome

AF:

0.0721

GnomAD4 exome

AF:

0.0670

AC:

97803

AN:

1459368

Hom.:

3673

Cov.:

AF XY:

0.0686

AC XY:

49797

AN XY:

726172

show subpopulations

African (AFR)

AF:

0.0528

AC:

1766

AN:

33442

American (AMR)

AF:

0.0332

AC:

1483

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0719

AC:

1878

AN:

26120

East Asian (EAS)

AF:

0.0271

AC:

1077

AN:

39686

South Asian (SAS)

AF:

0.110

AC:

9502

AN:

86204

European-Finnish (FIN)

AF:

0.0887

AC:

4737

AN:

53414

Middle Eastern (MID)

AF:

0.0753

AC:

434

AN:

5766

European-Non Finnish (NFE)

AF:

0.0657

AC:

72860

AN:

1109702

Other (OTH)

AF:

0.0674

AC:

4066

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

4427

8854

13281

17708

22135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2762

5524

8286

11048

13810

<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:

0.0612

AC:

9320

AN:

152262

Hom.:

317

Cov.:

AF XY:

0.0632

AC XY:

4704

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0532

AC:

2212

AN:

41556

American (AMR)

AF:

0.0375

AC:

573

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0779

AC:

270

AN:

3468

East Asian (EAS)

AF:

0.0341

AC:

177

AN:

5190

South Asian (SAS)

AF:

0.112

AC:

540

AN:

4832

European-Finnish (FIN)

AF:

0.0933

AC:

990

AN:

10606

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0641

AC:

4356

AN:

67998

Other (OTH)

AF:

0.0705

AC:

149

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

447

895

1342

1790

2237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0408

Hom.:

Bravo

AF:

0.0560

Asia WGS

AF:

0.0980

AC:

340

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 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

- -

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

-0.84

CADD

Benign

1.3

(source)

DANN

Benign

0.33

PhyloP100

0.044

PromoterAI

0.012

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