NEDD4
protein-codingNEDD4 E3 ubiquitin protein ligase, the group of HECT domain containing
Gene summary
This gene is the founding member of the NEDD4 family of HECT ubiquitin ligases that function in the ubiquitin proteasome system of protein degradation. The encoded protein contains an N-terminal calcium and phospholipid binding C2 domain followed by multiple tryptophan-rich WW domains and, a C-terminal HECT ubiquitin ligase catalytic domain. It plays critical role in the regulation of a number of membrane receptors, endocytic machinery components and the tumor suppressor PTEN. [provided by RefSeq, Jul 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~166.7 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 NEDD4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006154.4. 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 | 10 | 2 | 12 | |||
| missense | 106 | 6 | 1 | 113 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 0 | 113 | 16 | 3 | 132 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006145.2 | 29 | MANE Select | |
| Ensembl | ENSP00000410613.3 | 29 | MANE Select | |
| RefSeq | NP_001271267.1 | 25 | Standard | |
| RefSeq | NP_001271268.1 | 25 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endocytosis - Homo sapiens (human)
- Tight junction - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Epstein-Barr virus infection - Homo sapiens (human)
- IGF-Ncore
Biological Process
- protein polyubiquitination
- adaptive immune response
- outflow tract morphogenesis
- endocardial cushion development
- ubiquitin-dependent protein catabolic process
Molecular Function
- protein binding
- sodium channel inhibitor activity
- protein domain specific binding
- beta-2 adrenergic receptor binding
- ionotropic glutamate receptor binding
Cellular Component
- ubiquitin ligase complex
- chromatin
- cytoplasm
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000338963
- Coding exons
- 22
- Length
- 166825
- Individuals with no LoFs
- 125597
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 151
- Defined
- 125748
- p
- 0.000601
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.225 | 631 | 647 | 0.975 | 0.0000328 | 8195 |
| Missense (PolyPhen) | 207 | 253.86 | 0.81543 | 3182 | ||
| Synonymous | -0.185 | 232 | 228 | 1.02 | 0.0000115 | 2331 |
| Loss of Function | 4.08 | 32 | 68.4 | 0.468 | 0.00000384 | 805 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00064 | 0.00064 | rare |
| Ashkenazi Jewish | 0.00089 | 0.00089 | rare |
| East Asian | 0.00098 | 0.00098 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00062 | 0.00062 | rare |
| South Asian | 0.00053 | 0.00052 | rare |
| Other | 0.0016 | 0.0016 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins (PubMed:23644597). Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). {ECO:0000269|PubMed:11598133, ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:18562292, ECO:0000269|PubMed:20086093, ECO:0000269|PubMed:21399620, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:23644597, ECO:0000269|PubMed:25631046}.;
Recessive Scores
- pRec
- 0.211
Intolerance Scores
- LoFtool
- 0.553
- RVIS EVS
- 0.3
- RVIS percentile EVS
- 71.71
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.962
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |