AK7
protein-codingadenylate kinase 7, the group of Adenylate kinases|Cilia and flagella associated
Gene summary
This gene encodes a member of the adenylate kinase family of enzymes. The encoded enzyme is a phosphotransferase that catalyzes the reversible phosphorylation of adenine nucleotides. This enzyme plays a role in energy homeostasis of the cell. Alternative splicing results in multiple transcript variants. Mutations in the mouse gene are associated with primary ciliary dyskinesia. [provided by RefSeq, Apr 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~97.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0016575
Submitter: ClinGen
Primary Ciliary Dyskinesia (PCD) is a motile ciliopathy characterized by respiratory tract infections, body laterality defects and could be associated with infertility. Mutations in PCD patients have been identified in a heterogeneous group of genes normally expressed in cilia and/or sperm flagella (PMID: 33279404). The *AK7* (Adenylate kinase 7) gene was first reported in PCD patients in 2012 (PMID: 22801010), and in association with Spermatogenic failure 27 (MONDO:0054731, OMIM: 617965), in 2018 (PMID: 29365104). Per criteria outlined by the ClinGen Lumping and Splitting Working Group and due to the differences in molecular mechanism and the phenotypic variability, the ClinGen Motile Ciliopathy GCEP working group estimated that PCD (MONDO: 0016575) and Spermatogenic failure 27 (MONDO:0054731) represent distinct diseases and decided to split the entities. Evidence from four probands (PMID: 22801010 and PMID: 29365104) is included in this curation. However, in three patients, only a heterozygous mutation was detected (PMID: 22801010), and in the fourth patient mild respiratory signs, normal ciliary beating and normal ultrastructure were observed. Therefore, the score of the genetic evidence is downgraded to zero. AK7 is phosphotransferase that catalyzes the interconversion of nucleoside phosphates. This reaction provides energy for cellular processes requiring a stable supply of ATP, such as ciliary beating. The AK7 protein has a WcaG motif near the N terminus, followed by an AK domain and a C-terminal DPY30 motif. The WcaG motif is a signature of some prokaryotic nucleoside diphosphate sugar epimerases, and the DPY30 is a protein oligomerization motif. The expression pattern of *AK7* is similar to PCD-related genes which are particularly expressed in ciliated epithelia and sperm flagella (PMID: 25613900). In human nasal epithelial cell culture, Knockdown of* AK7* using siRNA caused a reduced *AK7* mRNA and protein levels and a decreased ciliary beat frequency (PMID: 20537283). *Ak7* knockout mice (Ak7 -/-) were generated by the insertion of a 4.5 kb transgene in the intron 5 of the AK7 gene (PMID: 18776131). No* Ak7* expression was detected in homozygous transgenic mice. (Ak7 -/-) mice showed growth retardation, hydrocephalus, and PCD signs, including airway dilatation and thickening of airway walls, and excess of mucus in the paranasal sinuses. Male Ak7 -/- mice were infertile. They lacked mature spermatids and spermatozoa, and electron microscopy showed abnormal sperm heads and absence of tail structures. Electron microscopy analysis of airway epithelial cells revealed reduced number of motile cilia, and cilia showed axonemes with central complex defect and microtubules disorganization. Using video microscopy, cilia of the airway epithelial cells showed a significantly reduced ciliary beat frequency (PMID: 18776131). Similar results were reported in (PMID: 21746835). In the patient reported in (PMID: 29365104), the expression of *AK7* was only altered in sperm. Compared to control, a normal expression pattern of *AK7* was observed in the patient’s airway epithelial cells. This experimental evidence **contradicts** the association of *AK7* with PCD. In summary, the evidence supporting the relationship between *AK7* and autosomal recessive PCD has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *AK7* plays in this disease.This classification was approved by the ClinGen Motile Ciliopathy GCEP on March 9, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0017173
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016575
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0004983
Submitter: ClinGen
Spermatogenic failure is characterized by male infertility due to morphologic abnormalities of the flagella (MMAF), including flagella that are short, absent, irregularly shaped, and coiled. Ultrastructural analysis shows loss of the central pair of microtubules, loss of the inner dynein arms, and peripheral doublet disorganization (PMID: 29365104). The *AK7* (Adenylate kinase 7) gene was first reported in association with Spermatogenic failure (MONDO:0054731, OMIM: 617965) in 2018 (PMID: 29365104), and in PCD patients in 2012 (PMID: 22801010). Per criteria outlined by the ClinGen Lumping and Splitting Working Group and due to the differences in molecular mechanism and the phenotypic variability, the ClinGen Motile Ciliopathy GCEP working group estimated that Spermatogenic failure (MONDO:0054731), and in PCD patients in 2012 (PMID: 22801010) represent distinct diseases and decided to split the entities. Evidence from two probands (PMID: 29365104 and PMID: 34854019) is included in this curation. Homozygous missense mutations were detected in both patients. Less than half a point (0.4) is reached with this genetic evidence. AK7 is phosphotransferase that catalyzes the interconversion of nucleoside phosphates. This reaction provides energy for cellular processes requiring a stable supply of ATP. The AK7 protein has a WcaG motif near the N terminus, followed by an AK domain and a C-terminal DPY30 motif. The WcaG motif is a signature of some prokaryotic nucleoside diphosphate sugar epimerases, and the DPY30 is a protein oligomerization motif. This gene-disease association is supported by experimental evidence. Abundant data confirms the expression of *AK7* in sperm flagella (PMID: 25613900, PMID: 29365104). Moreover, in patients with *AK7* mutations, the expression of the protein in sperm was altered (PMID: 29365104 and PMID: 34854019). *Ak7* knockout mice (Ak7 -/-) were generated by the insertion of a 4.5 kb transgene in the intron 5 of the *AK7* gene (PMID: 18776131). No *Ak7* expression was detected in homozygous transgenic mice. (Ak7 -/-) mice showed growth retardation, hydrocephalus, airway dilatation and thickening of airway walls, and excess of mucus in the paranasal sinuses. Male Ak7 -/- mice were infertile. They lacked mature spermatids and spermatozoa, and electron microscopy showed abnormal sperm heads and absence of tail structures (PMID: 18776131). Similar results were reported in (PMID: 21746835 and PMID: 29365104). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Motile Ciliopathy GCEP on March 9, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0054731
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Genitourinary
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AK7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152327.5. 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 | 5 | 89 | 6 | 100 | ||
| missense | 195 | 10 | 2 | 207 | ||
| nonsense | 11 | 11 | ||||
| start loss | 0 | |||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 8 | 9 | |||
| Total | 0 | 1 | 224 | 99 | 8 | 332 |
Highest pathogenic variant AF is 6.84727e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689540.2 | 18 | MANE Select | |
| Ensembl | ENSP00000267584.4 | 18 | MANE Select | |
| RefSeq | NP_001337817.1 | 17 | Standard | |
| RefSeq | NP_001337819.1 | 17 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Purine metabolism - Homo sapiens (human)
- Thiamine metabolism - Homo sapiens (human)
- adenosine ribonucleotides <i>de novo</i> biosynthesis
- Metabolism of nucleotides
- Interconversion of nucleotide di- and triphosphates
Biological Process
- nucleoside diphosphate phosphorylation
- nucleoside triphosphate biosynthetic process
- nucleobase-containing small molecule interconversion
- cell projection organization
- nucleoside monophosphate phosphorylation
Molecular Function
- adenylate kinase activity
- cytidylate kinase activity
- nucleoside diphosphate kinase activity
- ATP binding
- nucleoside kinase activity
Cellular Component
- cytosol
- motile cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000267584
- Coding exons
- 18
- Length
- 97317
- Individuals with no LoFs
- 125624
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 124
- Defined
- 125748
- p
- 0.000493
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.487 | 377 | 405 | 0.932 | 0.0000221 | 4778 |
| Missense (PolyPhen) | 93 | 115.49 | 0.80529 | 1423 | ||
| Synonymous | 0.763 | 142 | 154 | 0.922 | 0.00000923 | 1317 |
| Loss of Function | 2.33 | 27 | 43.6 | 0.619 | 0.00000254 | 500 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00044 | 0.00043 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00041 | 0.00040 | rare |
| East Asian | 0.0015 | 0.0015 | notable |
| Finnish | 0.0012 | 0.0012 | notable |
| European (Non-Finnish) | 0.00030 | 0.00029 | rare |
| South Asian | 0.00049 | 0.00049 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. Has highest activity toward AMP, and weaker activity toward dAMP, CMP and dCMP. Also displays broad nucleoside diphosphate kinase activity. Involved in maintaining ciliary structure and function. {ECO:0000269|PubMed:21080915, ECO:0000269|PubMed:23416111}.;
Recessive Scores
- pRec
- 0.160
Intolerance Scores
- LoFtool
- 0.514
- RVIS EVS
- -0.24
- RVIS percentile EVS
- 36.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0413
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |