8-11757012-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3PP5BS2

The NM_001308093.3(GATA4):c.1078G>A(p.Glu360Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GATA4
NM_001308093.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.06

Publications

9 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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

PP5

Variant 8-11757012-G-A is Pathogenic according to our data. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101. Variant chr8-11757012-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 30101.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3 link	c.1078G>A	p.Glu360Lys	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.1078G>A	p.Glu360Lys	missense_variant	Exon 6 of 7	1	NM_001308093.3	ENSP00000435712.1		P43694-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251414

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000448

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Sep 01, 2023

Laan Lab, Human Genetics Research Group, University of Tartu

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Ventricular septal defect 1

Pathogenic:1

Nov 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Atrioventricular septal defect 4

Uncertain:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 359 of the GATA4 protein (p.Glu359Lys). This variant is present in population databases (rs368489876, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 18672102, 21631294). ClinVar contains an entry for this variant (Variation ID: 30101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATA4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;T;D;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.77

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;.;M;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

N;N;N;N;.

REVEL

Pathogenic

0.76

Sift

Benign

0.27

T;T;T;T;.

Sift4G

Benign

0.84

T;T;T;T;T

Polyphen

1.0

.;.;D;.;.

Vest4

0.77

MVP

0.93

MPC

0.25

ClinPred

0.53

GERP RS

5.8

Varity_R

0.31

gMVP

0.64

Mutation Taster

=13/87

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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