19-10987920-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001387283.1(SMARCA4):c.1114T>C(p.Tyr372His) variant causes a missense change. The variant allele was found at a frequency of 0.0139 in 1,612,450 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y372N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 206 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 6.14

Publications

14 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=0.008926064).

BP6

Variant 19-10987920-T-C is Benign according to our data. Variant chr19-10987920-T-C is described in ClinVar as [Benign]. Clinvar id is 126355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0101 (1541/152168) while in subpopulation AMR AF = 0.0153 (233/15272). AF 95% confidence interval is 0.0144. There are 11 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 6 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.1114T>C	p.Tyr372His	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 6 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 7 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 6 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 6 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.1114T>C	p.Tyr372His	missense_variant	Exon 7 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.526T>C	p.Tyr176His	missense_variant	Exon 3 of 32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1541

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00329

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00961

AC:

2310

AN:

240404

AF XY:

0.00950

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00446

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0143

AC:

20822

AN:

1460282

Hom.:

206

Cov.:

AF XY:

0.0140

AC XY:

10145

AN XY:

726422

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33446

American (AMR)

AF:

0.0126

AC:

561

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.00261

AC:

225

AN:

86164

European-Finnish (FIN)

AF:

0.00498

AC:

263

AN:

52840

Middle Eastern (MID)

AF:

0.00761

AC:

AN:

5126

European-Non Finnish (NFE)

AF:

0.0169

AC:

18832

AN:

1111910

Other (OTH)

AF:

0.0128

AC:

770

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1108

2215

3323

4430

5538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0101

AC:

1541

AN:

152168

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

706

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00328

AC:

136

AN:

41518

American (AMR)

AF:

0.0153

AC:

233

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00187

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0152

AC:

1034

AN:

67992

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00278

AC:

ESP6500EA

AF:

0.0152

AC:

127

ExAC

AF:

0.00953

AC:

1153

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 02, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 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. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:3

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Coffin-Siris syndrome

Benign:2

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. -

Aug 16, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.039

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D

MetaRNN

Benign

0.0089

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.7

L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.20

N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.49

T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T

Sift4G

Benign

0.53

T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T

Polyphen

0.040

B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B

Vest4

0.52

MVP

0.91

MPC

1.7

ClinPred

0.0091

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.84

Mutation Taster

=98/2

polymorphism

(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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19-10987920-T-C

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