ADA

adenosine deaminase, the group of Adenosine deaminase family

Basic information

Region (hg38): 20:44584896-44652252

Links

ENSG00000196839

∙ NCBI:100 ∙ OMIM:608958 ∙ HGNC:186 ∙ Uniprot:P00813 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (Definitive), mode of inheritance: AR
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (Definitive), mode of inheritance: AR
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (Strong), mode of inheritance: AR
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (Supportive), mode of inheritance: AR
Omenn syndrome (Supportive), mode of inheritance: AR
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Severe combined immunodeficiency due to adenosine deaminase deficiency	AR	Allergy/Immunology/Infectious; Oncologic	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	Allergy/Immunology/Infectious; Oncologic	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
Variants may also contribute to Partial ADA deficiency; Gene therapy may be available, though largely on an experimental basis

ClinVar

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

Severe_combined_immunodeficiency,_autosomal_recessive,_T_cell-negative,_B_cell-negative,_NK_cell-negative,_due_to_adenosine_deaminase_deficiency (654 variants)
not_provided (67 variants)
not_specified (30 variants)
Severe_combined_immunodeficiency_disease (25 variants)
ADA-related_disorder (23 variants)
Partial_adenosine_deaminase_deficiency (8 variants)
Inborn_genetic_diseases (4 variants)
SCID_due_to_ADA_deficiency,_delayed_onset (3 variants)
Severe_combined_immunodeficiency,_autosomal_recessive,_T_cell-negative,_B_cell-negative,_NK_cell-positive (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ADA gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000022.4. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	6 clinvar	173 clinvar	1 clinvar	181
missense	10 clinvar	37 clinvar	140 clinvar	5 clinvar	1 clinvar	193
nonsense	15 clinvar	9 clinvar				24
start loss	1	1				2
frameshift	22 clinvar	25 clinvar	4 clinvar			51
splice donor/acceptor (+/-2bp)	13 clinvar	26 clinvar	5 clinvar			44
Total	61	99	155	178	2

Highest pathogenic variant AF is 0.00018276575

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ADA	protein_coding	protein_coding	ENST00000372874	12	32712

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.88e-12	0.0778	125679	0	69	125748	0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.118	199	204	0.977	0.0000126	2354
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000428	0.000420
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000219	0.000217
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000381	0.000378
Middle Eastern	0.000219	0.000217
South Asian	0.000313	0.000294
Other	0.00	0.00

dbNSFP

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.;
Pathway: Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;Primary immunodeficiency - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Purine Nucleoside Phosphorylase Deficiency;Mercaptopurine Action Pathway;Azathioprine Action Pathway;Xanthine Dehydrogenase Deficiency (Xanthinuria);Adenylosuccinate Lyase Deficiency;AICA-Ribosiduria;Thioguanine Action Pathway;Adenine phosphoribosyltransferase deficiency (APRT);Mitochondrial DNA depletion syndrome;Myoadenylate deaminase deficiency;Purine Metabolism;Molybdenum Cofactor Deficiency;Adenosine Deaminase Deficiency;Gout or Kelley-Seegmiller Syndrome;Lesch-Nyhan Syndrome (LNS);Xanthinuria type I;Xanthinuria type II;purine ribonucleosides degradation to ribose-1-phosphate;Metabolism of nucleotides;purine deoxyribonucleosides degradation;TCR;adenosine nucleotides degradation;purine nucleotides degradation;Metabolism;p73 transcription factor network;Nucleotide salvage;Purine salvage;Purine nucleotides nucleosides metabolism;superpathway of purine nucleotide salvage;Validated transcriptional targets of TAp63 isoforms;C-MYB transcription factor network;Validated transcriptional targets of deltaNp63 isoforms;adenine and adenosine salvage III (Consensus)

Recessive Scores

pRec: 0.684

Intolerance Scores

loftool: 0.172
rvis_EVS: -0.09
rvis_percentile_EVS: 46.92

Haploinsufficiency Scores

pHI: 0.111
hipred: N
hipred_score: 0.251
ghis: 0.515

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.966

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Ada
Phenotype: digestive/alimentary phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; embryo phenotype; respiratory system phenotype; liver/biliary system phenotype; hematopoietic 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); reproductive system 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); normal phenotype; endocrine/exocrine gland phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype;

Gene ontology

Biological process: response to hypoxia;histamine secretion;trophectodermal cell differentiation;liver development;placenta development;germinal center B cell differentiation;positive regulation of germinal center formation;negative regulation of leukocyte migration;negative regulation of mature B cell apoptotic process;adenosine catabolic process;deoxyadenosine catabolic process;cell adhesion;aging;purine ribonucleoside monophosphate biosynthetic process;positive regulation of heart rate;positive regulation of B cell proliferation;purine nucleotide salvage;positive regulation of T cell differentiation in thymus;response to vitamin E;regulation of cell-cell adhesion mediated by integrin;T cell activation;negative regulation of circadian sleep/wake cycle, non-REM sleep;response to hydrogen peroxide;purine-containing compound salvage;hypoxanthine salvage;response to morphine;positive regulation of smooth muscle contraction;dATP catabolic process;inosine biosynthetic process;xanthine biosynthetic process;positive regulation of alpha-beta T cell differentiation;lung alveolus development;Peyer's patch development;embryonic digestive tract development;negative regulation of inflammatory response;positive regulation of calcium-mediated signaling;positive regulation of T cell receptor signaling pathway;negative regulation of adenosine receptor signaling pathway;negative regulation of penile erection;negative regulation of thymocyte apoptotic process;negative regulation of mucus secretion
Cellular component: extracellular space;lysosome;cytosol;plasma membrane;external side of plasma membrane;cell surface;membrane;cell junction;dendrite cytoplasm;neuronal cell body;cytoplasmic vesicle lumen
Molecular function: purine nucleoside binding;adenosine deaminase activity;protein binding;zinc ion binding