NME4
protein-codingNME/NM23 nucleoside diphosphate kinase 4, the group of NME/NM23 family
Gene summary
The nucleoside diphosphate (NDP) kinases (EC 2.7.4.6) are ubiquitous enzymes that catalyze transfer of gamma-phosphates, via a phosphohistidine intermediate, between nucleoside and dioxynucleoside tri- and diphosphates. The enzymes are products of the nm23 gene family, which includes NME4 (Milon et al., 1997 [PubMed 9099850]).[supplied by OMIM, May 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NME4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005009.3. 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 | 1 | 2 | |||
| missense | 47 | 1 | 48 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 50 | 1 | 1 | 52 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005000.1 | 5 | MANE Select | |
| Ensembl | ENSP00000219479.2 | 5 | MANE Select | |
| RefSeq | NP_001273362.1 | 4 | Standard | |
| RefSeq | NP_001273364.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyrimidine metabolism - Homo sapiens (human)
- Drug metabolism - other enzymes - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
- Pyrimidine metabolism
- pyrimidine deoxyribonucleotides <i>de novo</i> biosynthesis
Biological Process
- nucleoside diphosphate phosphorylation
- GTP biosynthetic process
- UTP biosynthetic process
- CTP biosynthetic process
- lipid transport
Molecular Function
- nucleoside diphosphate kinase activity
- protein binding
- ATP binding
- metal ion binding
- cardiolipin binding
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- mitochondrial intermembrane space
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219479
- Coding exons
- 5
- Length
- 13643
- Individuals with no LoFs
- 125406
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125421
- p
- 0.0000598
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.740 | 138 | 116 | 1.19 | 0.00000811 | 1204 |
| Missense (PolyPhen) | 54 | 47.17 | 1.1448 | 464 | ||
| Synonymous | -1.79 | 61 | 45.6 | 1.34 | 0.00000317 | 394 |
| Loss of Function | 0.551 | 5 | 6.52 | 0.767 | 2.79e-7 | 82 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00060 | 0.00030 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000066 | 0.000046 | rare |
| European (Non-Finnish) | 0.00012 | 0.000079 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Through the catalyzed exchange of gamma- phosphate between di- and triphosphonucleosides participates in regulation of intracellular nucleotide homeostasis (PubMed:10799505). Binds to anionic phospholipids, predominantly to cardiolipin; the binding inhibits its phosphotransfer activity (PubMed:18635542, PubMed:23150663). Acts as mitochondria-specific NDK; its association with cardiolipin-containing mitochondrial inner membrane is coupled to respiration suggesting that ADP locally regenerated in the mitochondrion innermembrane space by its activity is directly taken up via ANT ADP/ATP translocase into the matrix space to stimulate respiratory ATP regeneration (PubMed:18635542). Proposed to increase GTP-loading on dynamin- related GTPase OPA1 in mitochondria (PubMed:24970086). In vitro can induce liposome cross-linking suggesting that it can cross- link inner and outer membranes to form contact sites, and promotes intermembrane migration of anionic phosphoplipids. Promotes the redistribution of cardiolipin between the mitochondrial inner membrane and outer membrane which is implicated in pro-apoptotic signaling (PubMed:18635542, PubMed:17028143, PubMed:23150663). {ECO:0000269|PubMed:10799505, ECO:0000269|PubMed:17028143, ECO:0000269|PubMed:18635542, ECO:0000269|PubMed:23150663, ECO:0000305, ECO:0000305|PubMed:24970086}.;
Recessive Scores
- pRec
- 0.149
Intolerance Scores
- LoFtool
- 0.695
- RVIS EVS
- -0.54
- RVIS percentile EVS
- 20.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0133
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |