ADK

protein-coding

adenosine kinase

Gene summary

This gene an enzyme which catalyzes the transfer of the gamma-phosphate from ATP to adenosine, thereby serving as a regulator of concentrations of both extracellular adenosine and intracellular adenine nucleotides. Adenosine has widespread effects on the cardiovascular, nervous, respiratory, and immune systems and inhibitors of the enzyme could play an important pharmacological role in increasing intravascular adenosine concentrations and acting as anti-inflammatory agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

MANE transcript

NM_006721.4

Inheritance

AR, AD

ClinVar variants

P:16U:60B:29

Top phenotype

Hypermethioninemia due to adenosine kinase deficiency

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr10:74,151,202-74,709,963

External References & Databases

Ensembl (ENSG00000156110)

Transcript & Mutation Effects

hg38 • Region Span ~558.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adenosine kinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100255

Submitter: G2P

adenosine kinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100255

Submitter: Labcorp Genetics (formerly Invitae)

adenosine kinase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100255

Submitter: ClinGen

ADK was first reported in relation to autosomal recessive Adenosine Kinase Deficiency in 2011 (Bjursell et al., PMID: 21963049). This disorder is multisystemic and includes phenotypes such as global developmental delay, seizures, hypotonia, recurrent hypoglycaemia, and prolonged hyperbilirubinemia in the neonatal period. At least eleven unique variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Methylation disorders are rarely reported, with ADK deficiency having only around twenty four confirmed cases in the literature reported in three publications (PMIDs: 21963049, 26642971, 33309011). This disorder was reported in several families with two siblings both displaying symptoms, however further segregation evidence is currently unavailable. The mechanism for disease is biallelic loss of function, with reduced ADK activity causing a buildup of adenosine, increasing the concentration of hepatic transaminases (ALAT, ASAT) and plasma AdoMet and AdoHcy, and leading to hyperbilirubinemia and hypermethionemia (PMID: 27671891). This pathway disruption causes a cascade of effects mainly in the liver and the brain via disruption of homeostasis, leading to hepatopathy and developmental delay/seizures (PMIDs: 11997462, 27903722). This gene-disease association is supported by the aforementioned biochemical function of ADK, primary protein/RNA expression in the liver and brain, and two knockout mouse models that each model a different aspect of the disorder. The global ADK knockout mice displayed significant liver abnormalities in the neonatal period, however the increased fatality rate did not allow for any observation of the neurological abnormalities. A later model introduced a brain-wide deletion only of ADK, succesfully recapitulating the increased seizures and behavioral/learning abnormalities commonly observed in human probands. In summary, ADK is definitively associated with autosomal recessive adenosine kinase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

adenosine kinase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100255

Submitter: Orphanet

adenosine kinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100255

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypermethioninemia due to adenosine kinase deficiencyAD

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Gastrointestinal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21963049

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADK variants in ClinVar

5 Conditions Cataloged

not providedTotal: 103

Adenosine kinase deficiencyTotal: 42

Inborn genetic diseasesTotal: 33

ADK-related disorderTotal: 13

not specifiedTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006721.4. 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			2 clinvar	27 clinvar	1 clinvar	30
missense	3 clinvar	2 clinvar	55 clinvar		1 clinvar	61
nonsense		2 clinvar				2
start loss		2 clinvar	1 clinvar			3
frameshift	2 clinvar	5 clinvar				7
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	5	11	60	27	2	105

Highest pathogenic variant AF is 0.000037932085

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006721.4	RefSeq	NP_006712.2	11	MANE Select
ENST00000539909.6	Ensembl	ENSP00000443965.2	11	MANE Select
NM_001123.4	RefSeq	NP_001114.2	11	Standard
NM_001202449.2	RefSeq	NP_001189378.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Purine metabolism - Homo sapiens (human)
Abacavir Pathway, Pharmacokinetics/Pharmacodynamics
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics
Mercaptopurine Action Pathway
Azathioprine Action Pathway

Biological Process

purine ribonucleoside salvage
dATP biosynthetic process
ribonucleoside monophosphate biosynthetic process
phosphorylation
purine-containing compound salvage

Molecular Function

RNA binding
adenosine kinase activity
ATP binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000286621
Coding exons: 11
Length: 558102
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125740
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.50	129	187	0.690	0.00000878	2404
Missense (PolyPhen)		28	61.495	0.45532		768
Synonymous	0.800	56	64.2	0.873	0.00000313	654
Loss of Function	2.23	9	19.7	0.457	9.14e-7	252

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides.;

Recessive Scores

pRec: 0.686

Intolerance Scores

LoFtool: 0.427
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.532

Gene Damage Prediction

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