ADA2
protein-codingadenosine deaminase 2, the group of Adenosine deaminase family
Gene summary
This gene encodes a member of a subfamily of the adenosine deaminase protein family. The encoded protein is one of two adenosine deaminases found in humans, which regulate levels of the signaling molecule, adenosine. The encoded protein is secreted from monocytes undergoing differentiation and may regulate cell proliferation and differentiation. This gene may be responsible for some of the phenotypic features associated with cat eye syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
- IDGFL
- CECR1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~79.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014306
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014306
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0015253
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008436
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014306
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014306
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100317
Submitter: ClinGen
*ADA2* (also known as *CECR1*) was first reported in relation to autosomal recessive deficiency of adenosine deaminase 2 (DADA2) in 2014 (Zhou Q, et al., 2014, PMID: 24552284). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is insufficient evidence of a difference in molecular mechanisms or inheritance pattern despite genotype:phenotype correlations that may explain the wide phenotypic spectrum observed from *ADA2* (PMID: 30406060, 31945408, 35095905, 37256629). Therefore, these entities were curated together under the umbrella term “deficiency of adenosine deaminase 2.” DADA2 is a heterogenous disease with variable expressivity that has different clinical manifestations including vasculitis, immune system dysregulation, and hematopoietic system impairment. Clinical features range from livedo racemosa, early-onset stroke, peripheral neuropathy, systemic vasculitis, musculoskeletal issues, and immune features such as systemic inflammation, severe bone marrow failure (severe B cell deficiency and pure red cell aplasia are among the most notable features), and immunodeficiency (PMID: 30406060, 31945408, 35095905, 35898506, 37179309, 37256629). DADA2 displays inter- and intrafamilial variability and penetrance is incomplete as asymptomatic individuals with biallelic *ADA2* variants have been reported (PMID: 26867732, 27059682, 31945408). ADA2 activity is much lower in individuals with biallelic pathogenic *ADA2* variants than in carriers and healthy controls (PMID: 32001434, 32054602, 32650798, 37256629). Notably, carriers of *ADA2* disease-causing variants have decreased ADA2 expression compared to healthy controls and there have been rare reports of carriers presenting with clinical features of DADA2 (PMID: 24552284, 29681619). Eleven variants (missense, in-frame indel, nonsense, frameshift, deletion) that have been reported in 8 probands in 5 publications (PMIDs: 24552284, 24737293, 28665179, 35774100, 35852217) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by experimental evidence, including an animal model, expression studies, and in vitro functional assays in both cell lines and patient-derived cells (PMIDs: 20453107, 24552284, 27663683, 32707604, 34004258, 35529868, 35663977). For example, ADA2 knockdown in a Zebrafish model resulted in increased bleeding and ischemia in the brain and neutropenia (PMID: 24552284). In an in vitro cell culture model, incubation of either a monocyte cell line lacking ADA2 expression or DADA2 patient-derived monocytes with an endothelial cell line resulted in damage to the endothelial cell layer (PMID: 24552284). DADA2 patient-derived B cells display decreased proliferation and immunoglobulin secretion following stimulation (PMID: 32707604). In a series of rescue experiments, transduction of DADA2 patient-derived hematopoietic stem cells or macrophages with a lentivirus carrying human ADA2 rescued features of disease, including decreased stem cell proliferation and stem cell and macrophage pro-inflammatory responses (PMID: 35529868). Hematopoietic cell transplantation has been demonstrated to rescue ADA2 activity and ameliorate hematological and immunological features with no new vascular events in DADA2 patients, particularly those presenting with bone marrow failure, immune cytopenia, malignancy, or immunodeficiency (PMID: 34324127, 35095905, 37256629). In summary, *ADA2* is definitively associated with autosomal recessive deficiency of adenosine deaminase 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0019170
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008436
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dermatologic
Intervention: Allergy/Immunology/Infectious
Rationale: Among other manifestations, individuals have been described as presenting with hypogammaglobulinemia, as well as recurrent bacterial and viral infections, and immunosuppressive treatment has been described as beneficial, though other manifestations have been described as recalcitrant to these types of therapies; Medical management (eg, with TNF inhibitor) has been described as beneficial.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ADA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001282225.2. 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 | 117 | 122 | ||
| missense | 11 | 31 | 236 | 9 | 1 | 288 |
| nonsense | 10 | 5 | 1 | 16 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 11 | 13 | 1 | 25 | ||
| splice donor/acceptor (+/-2bp) | 6 | 11 | 1 | 18 | ||
| Total | 40 | 62 | 243 | 126 | 1 | 472 |
Highest pathogenic variant AF is 0.000501804
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001269154.1 | 9 | MANE Select | |
| Ensembl | ENSP00000382731.2 | 9 | MANE Select | |
| RefSeq | NP_001269155.1 | 9 | Standard | |
| RefSeq | NP_001269156.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ada2b | Danio rerio | Structure: neutrophil Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Purine metabolism - Homo sapiens (human)
- Neutrophil degranulation
- Surfactant metabolism
- Metabolism of proteins
- Innate Immune System
Biological Process
- adenosine catabolic process
- multicellular organism development
- regulation of signaling receptor activity
- neutrophil degranulation
- cellular protein metabolic process
Molecular Function
- adenosine deaminase activity
- growth factor activity
- heparin binding
- zinc ion binding
- adenosine receptor binding
Cellular Component
- extracellular region
- extracellular space
- azurophil granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000399839
- Coding exons
- 9
- Length
- 42686
- Individuals with no LoFs
- 125667
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 80
- Defined
- 125747
- p
- 0.000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.357 | 280 | 297 | 0.942 | 0.0000159 | 3403 |
| Missense (PolyPhen) | 87 | 90.478 | 0.96156 | 1101 | ||
| Synonymous | 0.367 | 108 | 113 | 0.956 | 0.00000657 | 959 |
| Loss of Function | 1.32 | 14 | 20.5 | 0.684 | 0.00000104 | 239 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00061 | 0.00061 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00039 | 0.00039 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses. Requires elevated adenosine levels for optimal enzyme activity. Binds to cell surfaces via proteoglycans and may play a role in the regulation of cell proliferation and differentiation, independently of its enzyme activity. {ECO:0000269|PubMed:20147294, ECO:0000269|PubMed:20453107}.;
- Disease
- DISEASE: Polyarteritis nodosa (PAN) [MIM:615688]: A systemic necrotizing vasculitis that affects medium and small arteries. The ensuing tissue ischemia can affect any organ, including the skin, musculoskeletal system, kidneys, gastrointestinal tract, and the cardiovascular and nervous systems. Organ involvement and disease severity are highly variable. Clinical features include recurrent ischemic stroke affecting the small vessels of the brain and resulting in neurologic dysfunction, recurrent fever, myalgias, livedoid rash, gastrointestinal pain and hepatosplenomegaly. {ECO:0000269|PubMed:24552284, ECO:0000269|PubMed:24552285}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Sneddon syndrome (SNDDS) [MIM:182410]: A systemic non- inflammatory thrombotic vasculopathy characterized by the association of livedo racemosa, and in some cases livedo reticularis, with cerebrovascular disease. Livedo racemosa is a persistent net-like violaceous-cyanotic, mottled discoloration of the skin affecting the legs, the arms, the buttocks and the trunk; livedo reticularis is limited to the extremities and is visible only in the cold. Cerebrovascular features include recurrent transient ischemic attacks, infarcts, and rarely spinal strokes or intracranial or subarachnoid hemorrhages. Headache and vertigo may precede the onset of livedo racemosa and cerebrovascular manifestations by several years. Rare neurologic symptoms include seizures, chorea, or myelopathies. {ECO:0000269|PubMed:25075847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0931
Intolerance Scores
- RVIS EVS
- -0.35
- RVIS percentile EVS
- 29.43
Essentials
- Essential (gene trap)
- N