GATA4

GATA binding protein 4, the group of GATA zinc finger domain containing

Basic information

Region (hg38): 8:11676958-11760002

Links

ENSG00000136574 ∙ NCBI:2626 ∙ OMIM:600576 ∙ HGNC:4173 ∙ Uniprot:P43694 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• atrial septal defect 2 (Definitive), mode of inheritance: AD
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome (Strong), mode of inheritance: AD
• permanent neonatal diabetes mellitus (Strong), mode of inheritance: AD
• transient neonatal diabetes mellitus (Strong), mode of inheritance: AD
• neonatal diabetes mellitus (Strong), mode of inheritance: AD
• metabolic syndrome (Strong), mode of inheritance: AD
• testicular anomalies with or without congenital heart disease (Definitive), mode of inheritance: AD
• tetralogy of fallot (Supportive), mode of inheritance: AD
• familial atrial fibrillation (Supportive), mode of inheritance: AD
• 46,XY partial gonadal dysgenesis (Supportive), mode of inheritance: AD
• dilated cardiomyopathy (Limited), mode of inheritance: AD
• atrial septal defect 2 (Strong), mode of inheritance: AD
• structural congenital heart disease, multiple types - GATA4 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Atrioventricular septal defect 4; Ventricular septal defect 1; Atrial septal defect 2; Testicular anomalies with or without congenital heart disease; Tetralogy of Fallot	AD	Cardiovascular	Individuals may present with frank, obvious congenital cardiac malformations that require interventions, and more subtle presentations in individuals with have also been described, including valvular anomalies and arrhythmias, and surveillance (eg, with electrocardiogram and echocardiogram) may allow early detection and treatment of manifestations	Cardiovascular; Genitourinary	12845333; 15810002; 17643447; 18055909; 18672102; 20347099; 20659440; 21110066; 21220346; 21637914; 22101736; 22552926; 22648249

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GATA4 gene.

• Atrioventricular septal defect 4 (508 variants)
• not provided (180 variants)
• Cardiovascular phenotype (155 variants)
• not specified (34 variants)
• Congenital heart disease (15 variants)
• Testicular anomalies with or without congenital heart disease (12 variants)
• GATA4-related condition (11 variants)
• Atrial septal defect 2 (11 variants)
• Inborn genetic diseases (10 variants)
• Tetralogy of Fallot (7 variants)
• Ventricular septal defect 1 (7 variants)
• 46,XY sex reversal 3 (3 variants)
• Atrial septal defect 2;Tetralogy of Fallot;Testicular anomalies with or without congenital heart disease;Ventricular septal defect 1;Atrioventricular septal defect 4 (3 variants)
• Neonatal insulin-dependent diabetes mellitus (2 variants)
• Intellectual disability (2 variants)
• Ventricular septal defect 1;Atrial septal defect 2 (1 variants)
• Atrial septal defect 2;Testicular anomalies with or without congenital heart disease;Tetralogy of Fallot;Ventricular septal defect 1;Atrioventricular septal defect 4 (1 variants)
• Renal cysts and diabetes syndrome (1 variants)
• Thoracic aortic aneurysm (1 variants)
• Ventricular septal defect 1;Atrioventricular septal defect 4;Testicular anomalies with or without congenital heart disease;Atrial septal defect 2;Tetralogy of Fallot (1 variants)
• Transposition of the great arteries (1 variants)
• Microcephaly (1 variants)
• 11 conditions (1 variants)
• Atrial septal defect 2;Ventricular septal defect 1;Atrioventricular septal defect 4 (1 variants)
• Tetralogy of Fallot;Ventricular septal defect 1;Atrial septal defect 2;Testicular anomalies with or without congenital heart disease;Atrioventricular septal defect 4 (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Ventricular septal defect 1;Atrioventricular septal defect 4;Atrial septal defect 2;Testicular anomalies with or without congenital heart disease;Tetralogy of Fallot (1 variants)
• Testicular anomalies with or without congenital heart disease;Ventricular septal defect 1;Tetralogy of Fallot;Atrial septal defect 2;Atrioventricular septal defect 4 (1 variants)
• Pulmonic stenosis;Tricuspid regurgitation;Pulmonary valve atresia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GATA4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	179	3	184
missense	3	3	301	8	3	318
nonsense	6	1	1			8
start loss			1			1
frameshift		1	1			2
inframe indel			16			16
splice donor/acceptor (+/-2bp)						0
splice region			16	13	1	30
non coding			5	50	48	103
Total	9	5	327	237	54

Highest pathogenic variant AF is 0.0000131

Variants in GATA4

This is a list of pathogenic ClinVar variants found in the GATA4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
8-11703278-T-C		Atrioventricular septal defect 4	Likely benign (Aug 16, 2022)
8-11703355-C-A		Atrioventricular septal defect 4	Benign (Jul 25, 2022)
8-11703717-A-C			Benign (Sep 18, 2018)
8-11703850-C-T		GATA4-related disorder	Uncertain significance (Sep 12, 2022)
8-11703892-G-C			Likely benign (Oct 05, 2018)
8-11703892-G-T		GATA4-related disorder	Likely benign (Jun 15, 2023)
8-11703906-G-A		GATA4-related disorder	Likely benign (Apr 29, 2020)
8-11703967-G-A			Likely benign (Sep 22, 2018)
8-11703972-G-C			Benign (Sep 16, 2018)
8-11704219-C-T		Atrioventricular septal defect 4	Benign (Dec 11, 2023)
8-11704309-G-A		not specified	Benign (Feb 11, 2020)
8-11707578-C-A			Benign (Sep 11, 2018)
8-11708007-C-T			Likely benign (Apr 04, 2019)
8-11708019-G-T			Likely benign (Oct 17, 2018)
8-11708309-GACCATGT-G		Atrioventricular septal defect 4	Uncertain significance (Apr 30, 2022)
8-11708319-C-G			Uncertain significance (Sep 01, 2022)
8-11708320-A-C		Atrioventricular septal defect 4	Uncertain significance (Jan 05, 2024)
8-11708323-G-A		Atrioventricular septal defect 4	Uncertain significance (Sep 12, 2023)
8-11708324-C-A		Atrioventricular septal defect 4	Uncertain significance (May 25, 2023)
8-11708324-C-T		Atrioventricular septal defect 4	Likely benign (Jun 25, 2022)
8-11708325-T-C		Atrioventricular septal defect 4 • Cardiovascular phenotype	Likely benign (Nov 27, 2023)
8-11708327-G-A		Atrioventricular septal defect 4 • Cardiovascular phenotype	Likely benign (Jan 04, 2024)
8-11708331-A-G		Atrioventricular septal defect 4	Uncertain significance (Oct 25, 2022)
8-11708334-G-T		Atrioventricular septal defect 4	Uncertain significance (Aug 16, 2022)
8-11708335-C-A		Congenital heart disease	Pathogenic (May 15, 2013)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GATA4	protein_coding	protein_coding	ENST00000335135	6	83044

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.493	0.506	125743	0	4	125747	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.671	186	214	0.871	0.0000132	2767
Missense in Polyphen		40	74.49	0.53699		793
Synonymous	-2.35	123	94.1	1.31	0.00000670	965
Loss of Function	2.83	3	14.7	0.204	8.10e-7	169

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key role in cardiac development and function (PubMed:24000169, PubMed:27984724). In cooperation with TBX5, it binds to cardiac super-enhancers and promotes cardiomyocyte gene expression, while it downregulates endocardial and endothelial gene expression (PubMed:27984724). Involved in bone morphogenetic protein (BMP)-mediated induction of cardiac- specific gene expression. Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (By similarity). Acts as a transcriptional activator of ANF in cooperation with NKX2-5 (By similarity). Promotes cardiac myocyte enlargement (PubMed:20081228). Required during testicular development (PubMed:21220346). May play a role in sphingolipid signaling by regulating the expression of sphingosine-1-phosphate degrading enzyme, spingosine-1-phosphate lyase (PubMed:15734735). {ECO:0000250|UniProtKB:P46152, ECO:0000250|UniProtKB:Q08369, ECO:0000269|PubMed:15734735, ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:21220346, ECO:0000269|PubMed:24000169, ECO:0000269|PubMed:27984724}.
• Disease: DISEASE: Atrial septal defect 2 (ASD2) [MIM:607941]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Patients show other heart abnormalities including ventricular and atrioventricular septal defects, pulmonary valve thickening or insufficiency of the cardiac valves. The disease is not associated with defects in the cardiac conduction system or non-cardiac abnormalities. {ECO:0000269|PubMed:12845333, ECO:0000269|PubMed:15810002, ECO:0000269|PubMed:17643447, ECO:0000269|PubMed:18055909, ECO:0000269|PubMed:20347099, ECO:0000269|PubMed:20659440, ECO:0000269|PubMed:27984724}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ventricular septal defect 1 (VSD1) [MIM:614429]: A common form of congenital cardiovascular anomaly that may occur alone or in combination with other cardiac malformations. It can affect any portion of the ventricular septum, resulting in abnormal communications between the two lower chambers of the heart. Classification is based on location of the communication, such as perimembranous, inlet, outlet (infundibular), central muscular, marginal muscular, or apical muscular defect. Large defects that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death. {ECO:0000269|PubMed:18672102, ECO:0000269|PubMed:21110066, ECO:0000269|PubMed:21637914, ECO:0000269|PubMed:22101736}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tetralogy of Fallot (TOF) [MIM:187500]: A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. {ECO:0000269|PubMed:18672102, ECO:0000269|PubMed:21110066, ECO:0000269|PubMed:24000169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrioventricular septal defect 4 (AVSD4) [MIM:614430]: A congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum; the valve itself is also shared. A less severe form, known as ostium primum atrial septal defect, is characterized by separate atrioventricular valvar orifices despite a common junction. {ECO:0000269|PubMed:17643447}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Testicular anomalies with or without congenital heart disease (TACHD) [MIM:615542]: A 46,XY disorder of sex development with variable clinical presentation and defects in testicular differentiation and function. Clinical features include ambiguous genitalia, fused labioscrotal folds, hypospadias, microphallus, and bilateral inguinal hernia containing gonads. {ECO:0000269|PubMed:21220346}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=GATA4 mutations can predispose to dilated cardiomyopathy (CMD), a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:24041700, ECO:0000269|PubMed:25017055}.
• Pathway: Tight junction - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Physiological and Pathological Hypertrophy of the Heart;MicroRNAs in cardiomyocyte hypertrophy;Heart Development;Adipogenesis;Cardiac Progenitor Differentiation;Endoderm Differentiation;Serotonin Receptor 2 and ELK-SRF-GATA4 signaling;hop pathway in cardiac development;alk in cardiac myocytes;nfat and hypertrophy of the heart ;Factors involved in megakaryocyte development and platelet production;Hemostasis;Notch-mediated HES/HEY network (Consensus)

Recessive Scores

• pRec: 0.712

Haploinsufficiency Scores

• pHI: 0.954
• hipred: Y
• hipred_score: 0.875
• ghis: 0.470

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.956

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gata4
• Phenotype: growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; embryo phenotype; liver/biliary system phenotype; respiratory system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: gata4
• Affected structure: caudal vein plexus
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: heart looping;aortic valve morphogenesis;endocardial cushion development;cardiac ventricle morphogenesis;cardiac right ventricle morphogenesis;ventricular septum development;atrial septum primum morphogenesis;atrial septum secundum morphogenesis;regulation of transcription, DNA-templated;transcription by RNA polymerase II;cell-cell signaling;endoderm development;blood coagulation;male gonad development;response to mechanical stimulus;negative regulation of autophagy;positive regulation of vascular endothelial growth factor production;positive regulation of BMP signaling pathway;response to vitamin A;embryonic heart tube anterior/posterior pattern specification;response to drug;positive regulation of angiogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;embryonic foregut morphogenesis;cardiac muscle tissue development;positive regulation of cardioblast differentiation;transdifferentiation;atrial septum morphogenesis;intestinal epithelial cell differentiation;cell growth involved in cardiac muscle cell development;cellular response to glucose stimulus;regulation of cardiac muscle cell contraction
• Cellular component: nucleus;nucleoplasm;nuclear body;RNA polymerase II transcription factor complex
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II transcription factor binding;enhancer sequence-specific DNA binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;transcription coactivator activity;protein binding;transcription factor binding;zinc ion binding;protein kinase binding;activating transcription factor binding;sequence-specific DNA binding;transcription regulatory region DNA binding;NFAT protein binding;co-SMAD binding