rs3729856

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001308093.3(GATA4):c.1132A>G(p.Ser378Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,614,072 control chromosomes in the GnomAD database, including 11,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.089 ( 848 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10216 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:11

Conservation

PhyloP100: 0.363

Publications

53 publications found

Variant links:

Genes affected

GATA4 (HGNC:4173): (GATA binding protein 4) This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

GATA4 Gene-Disease associations (from GenCC):

atrial septal defect 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
structural congenital heart disease, multiple types - GATA4
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
testicular anomalies with or without congenital heart disease
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
metabolic syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
pancreatic hypoplasia-diabetes-congenital heart disease syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
permanent neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
transient neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tetralogy of fallot
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

GATA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017141104).

BP6

Variant 8-11757066-A-G is Benign according to our data. Variant chr8-11757066-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44334.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3 link	c.1132A>G	p.Ser378Gly	missense_variant	Exon 6 of 7	ENST00000532059.6	NP_001295022.1	P43694-2B3KUF4B6DU75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6 link	c.1132A>G	p.Ser378Gly	missense_variant	Exon 6 of 7	1	NM_001308093.3	ENSP00000435712.1		P43694-2

Frequencies

GnomAD3 genomes

AF:

0.0887

AC:

13494

AN:

152210

Hom.:

848

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.0956

Gnomad AMR

AF:

0.0530

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0488

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.0893

GnomAD2 exomes

AF:

0.0952

AC:

23909

AN:

251156

AF XY:

0.0966

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.0421

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.112

AC:

163346

AN:

1461744

Hom.:

10216

Cov.:

AF XY:

0.112

AC XY:

81236

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0198

AC:

662

AN:

33474

American (AMR)

AF:

0.0459

AC:

2052

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

4621

AN:

26134

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.0564

AC:

4865

AN:

86254

European-Finnish (FIN)

AF:

0.145

AC:

7762

AN:

53374

Middle Eastern (MID)

AF:

0.138

AC:

793

AN:

5764

European-Non Finnish (NFE)

AF:

0.122

AC:

136088

AN:

1111944

Other (OTH)

AF:

0.108

AC:

6494

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

9141

18283

27424

36566

45707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4610

9220

13830

18440

23050

<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:

0.0885

AC:

13487

AN:

152328

Hom.:

848

Cov.:

AF XY:

0.0868

AC XY:

6465

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0210

AC:

874

AN:

41576

American (AMR)

AF:

0.0528

AC:

808

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

639

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5186

South Asian (SAS)

AF:

0.0487

AC:

235

AN:

4828

European-Finnish (FIN)

AF:

0.140

AC:

1490

AN:

10608

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9131

AN:

68030

Other (OTH)

AF:

0.0874

AC:

185

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

650

1299

1949

2598

3248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.116

Hom.:

4719

Bravo

AF:

0.0783

TwinsUK

AF:

0.116

AC:

429

ALSPAC

AF:

0.111

AC:

427

ESP6500AA

AF:

0.0236

AC:

104

ESP6500EA

AF:

0.140

AC:

1204

ExAC

AF:

0.0959

AC:

11648

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser377Gly in exon 6 of GATA4: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It h as been identified in 14% (927/6596) of European chromosomes, including 67 homoz ygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs3729856). -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1Benign:3

Sep 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30229885, 28541271, 23626780, 28161810, 27064867) -

Nov 13, 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

- -

Molecular Genetics and Enzymology, National Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neonatal insulin-dependent diabetes mellitus

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in GATA4 gene are associated with neonatal diabetes, decreased insulin production due to pancreatic aplasia or hypoplasia. Also associated with isolated cardiac abnormalities in children, like atrial septal defects. However no sufficient evidence is found to ascertain the role of this particular variant rs3729856 yet. -

Atrioventricular septal defect 4

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 23, 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

Benign

0.068

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.23

CADD

Benign

1.5

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

T;T;T;.;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.52

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

-0.20

.;.;N;.;.

PhyloP100

0.36

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.39

N;N;N;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.42

T;T;T;T;.

Sift4G

Benign

0.47

T;T;T;T;T

Polyphen

0.0

.;.;B;.;.

Vest4

0.081

MPC

0.16

ClinPred

0.0016

GERP RS

0.91

Varity_R

0.044

gMVP

0.40

Mutation Taster

=94/6

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