rs3729856

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:10

Conservation

PhyloP100: 0.363

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 44334.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr8-11757066-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
GATA4	NM_001308093.3 linkuse as main transcript	c.1132A>G	p.Ser378Gly	missense_variant	6/7	ENST00000532059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA4	ENST00000532059.6 linkuse as main transcript	c.1132A>G	p.Ser378Gly	missense_variant	6/7	1	NM_001308093.3	A1	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

GnomAD3 exomes

AF:

0.0952

AC:

23909

AN:

251156

Hom.:

1527

AF XY:

0.0966

AC XY:

13123

AN XY:

135814

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 SAS exome

AF:

0.0552

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

Gnomad4 AFR exome

AF:

0.0198

Gnomad4 AMR exome

AF:

0.0459

Gnomad4 ASJ exome

AF:

0.177

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0564

Gnomad4 FIN exome

AF:

0.145

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.108

GnomAD4 genome

AF:

0.0885

AC:

13487

AN:

152328

Hom.:

848

Cov.:

AF XY:

0.0868

AC XY:

6465

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0210

Gnomad4 AMR

AF:

0.0528

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.0487

Gnomad4 FIN

AF:

0.140

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.0874

Alfa

AF:

0.122

Hom.:

2461

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:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 13, 2016	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

not provided

Pathogenic:1Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely pathogenic, no assertion criteria provided	literature only	Molecular Genetics and Enzymology, National Research Centre	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	This variant is associated with the following publications: (PMID: 30229885, 28541271, 23626780, 28161810, 27064867) -

Neonatal insulin-dependent diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

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

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

MutationTaster

Benign

0.40

P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over