GATA2
protein-codingGATA binding protein 2, the group of GATA zinc finger domain containing
Gene summary
This gene encodes a member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide sequence they bind in the promoter regions of target genes. The encoded protein plays an essential role in regulating transcription of genes involved in the development and proliferation of hematopoietic and endocrine cell lineages. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0042982
Submitter: ClinGen
GATA2 was first reported in relation to autosomal dominant GATA2-deficiency with susceptibility to myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) in 2011. This occurred over several publications, referring to the condition as Emberger Syndrome, when presenting with primary lymphedema (Ostergaard et al., 2011 PMID 21892158), familial MDS (Hahn et al., 2011 PMID 21895162), DCML deficiency (Dickinson et al., 2011 PMID: 21765025, 21810969), and MonoMac (Hsu et al., 2011 PMID 21670465). In addition, Warts, Immunodeficiency, Lymphedema, and anogenital Dysplasia (WILD) syndrome (PMID: 28373026) is another clinical entity described in the literature that falls under the umbrella of GATA2 deficiency with susceptibility to MDS/AML. Due to the deficiency of several white blood cell subsets (B cells, NK cells, dendritic cells, monocytes, CD4+ T cells) (PMID: 30047422, 23365458) and susceptibility to viral, bacterial and fungal infections (PMID: 25397911), as well as the presence of dysplastic megakaryocytes in the bone marrow (PMID: 30047422) and other phenotypes such as pulmonary alveolar proteinosis (PMID: 34089740), the GATA2 gene, and associated haploinsufficiency is considered an inborn error of immunity (Tangye S et al., 2020 PMID 31953710). At least 40 variants (including missense, nonsense, frameshift, and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 19 probands in 7 publications (PMIDs: 21892158, 21895162, 21670465, 22147895, 23223431, 23502222, 25624456). Variants in this gene segregated with disease in 46 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hsu et al., 2013 PMID 23502222). This gene-disease association is supported by its biochemical function as part of the transcriptional program for blood (Gottgens et al., 2002 PMID 12065417), expression in hematopoietic cells (Kazenwadel et al., 2012 PMID 22147895), functional alteration in both patient and non-patient cells leading to altered gene expression (PMIDs: 21892162, 23502222, 25624456), and two mouse model organisms with limited utility due to lethality (PMIDs: 8078582, 22996665). In summary GATA2 is definitively associated with autosomal dominant GATA2-deficiency with susceptibility to MDS/AML. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, or phenotypic variability underlying the these many disease entities: Emberger Syndrome (MIM 614038), Immunodeficiency 21 (MIM 614172), susceptibility to acute myeloid leukemia (MIM 601626) and susceptibility to Myelodysplastic syndrome (MIM 614286). Today it is well accepted that all these clinical manifestations belong to the broad spectrum of a single genetic disease; the term GATA2 deficiency or haploinsufficiency has been widely accepted to describe GATA2-related disorders (Wlodarski et al., 2017 PMID 28637621). Therefore, all of the disease entities have been lumped into one disease entity, dominant GATA2-deficiency with susceptibility to MDS/AML.
Inheritance Pattern: AD
Disease ID:MONDO:0013540
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013540
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013607
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0042982
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013607
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013540
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0018874
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0018881
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dermatologic; Hematologic; Oncologic; Pulmonary
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Oncologic
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Surveillance for myelodysplastic syndrome and related oncologic processes (eg, acute myeloid leukemia) may allow early diagnosis and treatment, which may reduce morbidity and mortality; In Lymphedema, primary, with myelodsyplasia (Emberger syndrome), early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GATA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032638.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 4 | 434 | 2 | 441 | |
| missense | 8 | 49 | 859 | 40 | 2 | 958 |
| nonsense | 22 | 11 | 33 | |||
| start loss | 4 | 4 | ||||
| frameshift | 102 | 28 | 7 | 137 | ||
| splice donor/acceptor (+/-2bp) | 11 | 11 | 1 | 23 | ||
| Total | 144 | 99 | 875 | 474 | 4 | 1596 |
Highest pathogenic variant AF is 0.000006572634
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_116027.2 | 5 | MANE Select | |
| Ensembl | ENSP00000345681.2 | 5 | MANE Select | |
| RefSeq | NP_001139133.1 | 5 | MANE Plus Clinical | |
| RefSeq | NP_001139134.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gata2a | Danio rerio | Structure: nucleate erythrocyte Quality: accumulation abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- White fat cell differentiation
- Adipogenesis
- Hematopoietic Stem Cell Differentiation
- Preimplantation Embryo
- White fat cell differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- urogenital system development
- cell fate determination
- neuron migration
- embryonic placenta development
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- enhancer sequence-specific DNA binding
- DNA-binding transcription activator activity, RNA polymerase II-specific
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000341105
- Coding exons
- 5
- Length
- 13759
- Individuals with no LoFs
- 104874
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 104875
- p
- 0.00000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.04 | 195 | 293 | 0.665 | 0.0000155 | 3055 |
| Missense (PolyPhen) | 111 | 181.17 | 0.61269 | 1905 | ||
| Synonymous | -1.40 | 151 | 131 | 1.16 | 0.00000732 | 1026 |
| Loss of Function | 3.51 | 1 | 16.3 | 0.0615 | 7.96e-7 | 186 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000011 | 0.000011 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells. Binds to the consensus sequence 5'-AGATAG-3'.;
- Disease
- DISEASE: Lymphedema, primary, with myelodysplasia (LMPM) [MIM:614038]: A chronic disabling condition characterized by swelling of the extremities due to altered lymphatic flow, associated with myelodysplasia. Patients with lymphedema suffer from recurrent local infections, and physical impairment. {ECO:0000269|PubMed:21892158}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myelodysplastic syndrome (MDS) [MIM:614286]: A heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular bone marrow with impaired morphology and maturation, dysplasia of the myeloid, megakaryocytic and/or erythroid lineages, and peripheral blood cytopenias resulting from ineffective blood cell production. Included diseases are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative disease. MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML). {ECO:0000269|PubMed:21892162}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.635
Intolerance Scores
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.56
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |