ADA

protein-coding

adenosine deaminase, the group of Adenosine deaminase family

Gene summary

This gene encodes an enzyme that catalyzes the hydrolysis of adenosine to inosine in the purine catabolic pathway. Various mutations have been described for this gene and have been linked to human diseases related to impaired immune function such as severe combined immunodeficiency disease (SCID) which is the result of a deficiency in the ADA enzyme. In ADA-deficient individuals there is a marked depletion of T, B, and NK lymphocytes, and consequently, a lack of both humoral and cellular immunity. Conversely, elevated levels of this enzyme are associated with congenital hemolytic anemia. [provided by RefSeq, Sep 2019]

MANE transcript

NM_000022.4

Inheritance

ClinVar variants

P:179U:172B:188

Top phenotype

Severe combined immunodeficiency due to adenosine deaminase deficiency

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr20:44,584,896-44,652,252

External References & Databases

Ensembl (ENSG00000196839)

Transcript & Mutation Effects

hg38 • Region Span ~67.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: ClinGen

Adenosine deaminase deficiency in relation to severe combined immunodeficiency (SCID) was first reported in the 1970s, then in 1985 Bonthron et al. (PMID: 3839802) identified the first variant in ADA. The relationship of ADA to autosomal recessive adenosine deaminase deficiency was confirmed by the first report of biallelic variants from Akeson et al., 1987 (PMID: 3475710). ADA deficiency is associated with a cellular SCID phenotype that is low in T cells, B cells, and NK cells. ADA deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable effects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental effects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected SCID patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency (reviewed in PMID: 29690908). However, there is heterogeneity in the phenotype of ADA-deficiency, with approximately 15–20% of patients exhibiting a delayed clinical onset, presenting with less severe combined immune deficiency later in life, hypomorphic variants are often identified in such patients. Additionally, healthy individuals with absence of ADA in erythrocytes but retention of readily detectable ADA in non-erythroid cells (partial ADA deficiency) have also been identified. Over 80 unique variants have been reported in humans (predominantly missense, as well as nonsense, frameshift, splicing, small indels, and gross deletions). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seventeen unique variants from 13 probands in 6 publications were curated (PMIDs: 29690908, 10200056, 7691348, 9225964, 9108404, 7599635). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by its role in catalyzing the hydrolytic deamination of adenosine to inosine (PMID: 8452534), preventing accumulation of the cytotoxic metabolite deoxyadenosine, and its altered function in patient cells (PMID: 627115). Further support is provided by recapitulation of human disease in a mouse model (PMID: 9478961), as well as the rescue of the mouse model by either enzyme therapy (PMID: 10908569) or gene therapy (PMID: 16835374). Additionally, both enzyme therapy (PMID: 3807953) and gene therapy (PMID: 19179314) have shown rescue of the phenotype in patients. In summary ADA is definitively associated with autosomal recessive adenosine deaminase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Omenn syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011338

Submitter: Orphanet

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: Orphanet

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: Natera

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: PanelApp Australia

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: Labcorp Genetics (formerly Invitae)

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: Myriad Women's Health

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007064

Submitter: G2P

Clinical Genomic Database (CGD)

Severe combined immunodeficiency due to adenosine deaminase deficiencyAR

Manifestation: Allergy/Immunology/Infectious; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Enzyme treatment (with PEG-ADA) is beneficial; Antiinfectious prophylaxis and early and aggressive treatment of infections are indicated; BMT has been described in many individuals; Surveillance for certain neoplasms may be beneficial

Comments: Variants may also contribute to Partial ADA deficiency; Gene therapy may be available, though largely on an experimental basis

Refs: 4117384; 46025; 1089883; 978319; 18618; 980079; 477037; 38963; 7436484; 6863546; 3781559; 3946419; 3007108; 3475710; 3807953; 3260944; 2783588; 2166947; 8227344; 8099155; 8051429; 1974554; 8023852; 8120281; 9108404; 10021471; 12089448; 14499267; 16905365; 19638621; 21725047; 21865538; 22153773; 22348551; 22447032; 22791287; 22805442; 22968453; 23118212; 23895897

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADA variants in ClinVar

11 Conditions Cataloged

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencyTotal: 699

not providedTotal: 97

not specifiedTotal: 62

ADA-related disorderTotal: 45

Severe combined immunodeficiency diseaseTotal: 28

Partial adenosine deaminase deficiencyTotal: 8

Inborn genetic diseasesTotal: 6

SCID due to ADA deficiency, delayed onsetTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000022.4. 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			7 clinvar	179 clinvar	1 clinvar	187
missense	12 clinvar	39 clinvar	151 clinvar	7 clinvar	1 clinvar	210
nonsense	17 clinvar	10 clinvar	1 clinvar			28
start loss	1 clinvar	2 clinvar	1 clinvar			4
frameshift	31 clinvar	25 clinvar	4 clinvar			60
splice donor/acceptor (+/-2bp)	13 clinvar	29 clinvar	8 clinvar			50
Total	74	105	172	186	2	539

Highest pathogenic variant AF is 0.00018276575

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000022.4	RefSeq	NP_000013.2	12	MANE Select
ENST00000372874.9	Ensembl	ENSP00000361965.4	12	MANE Select
NM_001322050.2	RefSeq	NP_001308979.1	8	Standard
NM_001322051.2	RefSeq	NP_001308980.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antimetabolite Pathway - Folate Cycle, Pharmacodynamics
Primary immunodeficiency - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Methotrexate Pathway (Cancer Cell), Pharmacodynamics
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics

Biological Process

response to hypoxia
histamine secretion
trophectodermal cell differentiation
liver development
placenta development

Molecular Function

purine nucleoside binding
adenosine deaminase activity
protein binding
zinc ion binding

Cellular Component

extracellular space
lysosome
cytosol
plasma membrane
external side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372874
Coding exons: 12
Length: 32712
Individuals with no LoFs: 125679
Homozygous LoFs: 0
Heterozygous LoFs: 69
Defined: 125748
p: 0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.118	199	204	0.977	0.0000126	2354
Missense (PolyPhen)		83	81.984	1.0124		947
Synonymous	-0.500	91	85.1	1.07	0.00000593	684
Loss of Function	0.425	19	21.1	0.900	0.00000111	247

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00031	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the hydrolytic deamination of adenosine and 2- deoxyadenosine (PubMed:8452534, PubMed:16670267). Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4 (PubMed:20959412). Its interaction with DPP4 regulates lymphocyte- epithelial cell adhesion (PubMed:11772392). Enhances dendritic cell immunogenicity by affecting dendritic cell costimulatory molecule expression and cytokines and chemokines secretion (By similarity). Enhances CD4+ T-cell differentiation and proliferation (PubMed:20959412). Acts as a positive modulator of adenosine receptors ADORA1 and ADORA2A, by enhancing their ligand affinity via conformational change (PubMed:23193172). Stimulates plasminogen activation (PubMed:15016824). Plays a role in male fertility (PubMed:21919946, PubMed:26166670). Plays a protective role in early postimplantation embryonic development (By similarity). {ECO:0000250|UniProtKB:P03958, ECO:0000250|UniProtKB:P56658, ECO:0000269|PubMed:11772392, ECO:0000269|PubMed:15016824, ECO:0000269|PubMed:16670267, ECO:0000269|PubMed:20959412, ECO:0000269|PubMed:21919946, ECO:0000269|PubMed:23193172, ECO:0000269|PubMed:26166670, ECO:0000269|PubMed:8452534}.;
Disease: DISEASE: Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-negative/NK-cell-negative due to adenosine deaminase deficiency (ADASCID) [MIM:102700]: An autosomal recessive disorder accounting for about 50% of non-X-linked SCIDs. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell- mediated cellular immunity due to a defect in T-cell development. ADA deficiency has been diagnosed in chronically ill teenagers and adults (late or adult onset). Population and newborn screening programs have also identified several healthy individuals with normal immunity who have partial ADA deficiency. {ECO:0000269|PubMed:10200056, ECO:0000269|PubMed:1284479, ECO:0000269|PubMed:2166947, ECO:0000269|PubMed:2783588, ECO:0000269|PubMed:3182793, ECO:0000269|PubMed:3839802, ECO:0000269|PubMed:6208479, ECO:0000269|PubMed:7599635, ECO:0000269|PubMed:8227344, ECO:0000269|PubMed:8299233, ECO:0000269|PubMed:9361033}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.684

Intolerance Scores

LoFtool: 0.172
RVIS EVS: -0.09
RVIS percentile EVS: 46.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.966

Gene Damage Prediction

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