NEDD4

NEDD4 E3 ubiquitin protein ligase, the group of HECT domain containing

Basic information

Region (hg38): 15:55826921-55993660

Links

ENSG00000069869 ∙ NCBI:4734 ∙ OMIM:602278 ∙ HGNC:7727 ∙ Uniprot:P46934 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NEDD4 gene.

• Inborn genetic diseases (52 variants)
• not provided (31 variants)
• not specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NEDD4 gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				10	7	17
missense			45	11	7	63
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				2	1	3
non coding				1		1
Total	0	0	45	22	14

Variants in NEDD4

This is a list of pathogenic ClinVar variants found in the NEDD4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-55829931-A-G		NEDD4-related disorder	Likely benign (Jul 08, 2022)
15-55829975-A-T			Likely benign (Mar 01, 2023)
15-55830580-T-C		not specified	Uncertain significance (Nov 17, 2022)
15-55830589-A-G			Likely benign (Dec 18, 2018)
15-55833032-T-C		not specified	Uncertain significance (Oct 05, 2022)
15-55833039-C-T			Likely benign (Oct 29, 2018)
15-55833092-T-C		not specified	Uncertain significance (Jun 12, 2023)
15-55834082-T-G		not specified	Uncertain significance (Jun 29, 2023)
15-55834113-C-T			Benign (Dec 31, 2019)
15-55834252-T-C			Likely benign (Mar 01, 2023)
15-55837832-C-T		not specified	Uncertain significance (Feb 28, 2023)
15-55838124-G-C		not specified	Uncertain significance (Feb 28, 2024)
15-55840475-G-C		not specified	Uncertain significance (Dec 28, 2022)
15-55840506-G-A		not specified	Uncertain significance (Jun 29, 2022)
15-55840613-C-G			Likely benign (May 17, 2018)
15-55840651-C-T		not specified	Uncertain significance (Dec 03, 2021)
15-55842006-G-C		not specified	Uncertain significance (Apr 28, 2022)
15-55848395-C-T		not specified	Uncertain significance (Mar 01, 2024)
15-55848436-G-A			Likely benign (May 25, 2018)
15-55848548-C-T		not specified	Uncertain significance (Nov 06, 2023)
15-55848825-T-C		not specified	Likely benign (Jan 23, 2023)
15-55850574-A-C		not specified	Uncertain significance (May 01, 2022)
15-55850602-G-T			Likely benign (Dec 31, 2019)
15-55850627-C-A		not specified	Uncertain significance (Jul 27, 2022)
15-55850636-A-G		not specified	Uncertain significance (Dec 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NEDD4	protein_coding	protein_coding	ENST00000338963	22	166825

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.72e-13	1.00	125597	0	151	125748	0.000601

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.225	631	647	0.975	0.0000328	8195
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000888	0.000884
Ashkenazi Jewish	0.000894	0.000893
East Asian	0.000984	0.000979
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000621	0.000615
Middle Eastern	0.000984	0.000979
South Asian	0.000525	0.000523
Other	0.00163	0.00163

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Endocytosis - Homo sapiens (human);Tight junction - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);IGF-Ncore;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;miR-targeted genes in squamous cell - TarBase;Proteasome Degradation;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;EGF-EGFR Signaling Pathway;Signal Transduction;Regulation of PTEN localization;Regulation of PTEN stability and activity;Cytokine Signaling in Immune system;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Downregulation of ERBB4 signaling;Class I MHC mediated antigen processing & presentation;ErbB4 signaling events;EGFR1;PTEN Regulation;PIP3 activates AKT signaling;Signaling by ERBB4;Signaling by Receptor Tyrosine Kinases;Intracellular signaling by second messengers;ISG15 antiviral mechanism;Antiviral mechanism by IFN-stimulated genes;Interferon Signaling;Signaling events mediated by VEGFR1 and VEGFR2 (Consensus)

Recessive Scores

• pRec: 0.211

Intolerance Scores

• loftool: 0.553
• rvis_EVS: 0.3
• rvis_percentile_EVS: 71.71

Haploinsufficiency Scores

• pHI: 0.305
• hipred: Y
• hipred_score: 0.684
• ghis: 0.532

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.962

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nedd4
• 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); 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); immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); growth/size/body region phenotype

Gene ontology

• Biological process: protein polyubiquitination;adaptive immune response;outflow tract morphogenesis;endocardial cushion development;ubiquitin-dependent protein catabolic process;protein monoubiquitination;protein targeting to lysosome;lysosomal transport;neuromuscular junction development;negative regulation of sodium ion transport;negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage;positive regulation of phosphatidylinositol 3-kinase signaling;regulation of macroautophagy;protein ubiquitination;transmission of virus;negative regulation of vascular endothelial growth factor receptor signaling pathway;neuron projection development;receptor internalization;receptor catabolic process;cellular response to UV;regulation of ion transmembrane transport;T cell activation;regulation of membrane potential;glucocorticoid receptor signaling pathway;proteasome-mediated ubiquitin-dependent protein catabolic process;ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway;development involved in symbiotic interaction;positive regulation of protein catabolic process;positive regulation of nucleocytoplasmic transport;blood vessel morphogenesis;regulation of dendrite morphogenesis;regulation of synapse organization;progesterone receptor signaling pathway;response to calcium ion;protein K63-linked ubiquitination;regulation of potassium ion transmembrane transporter activity;negative regulation of sodium ion transmembrane transporter activity
• Cellular component: ubiquitin ligase complex;chromatin;cytoplasm;Golgi apparatus;cytosol;plasma membrane;cell cortex;apicolateral plasma membrane;dendritic spine;perinuclear region of cytoplasm;extracellular exosome;glutamatergic synapse;postsynaptic cytosol
• Molecular function: protein binding;sodium channel inhibitor activity;protein domain specific binding;beta-2 adrenergic receptor binding;ionotropic glutamate receptor binding;ubiquitin binding;phosphoserine residue binding;phosphothreonine residue binding;ubiquitin protein ligase activity;RNA polymerase binding;proline-rich region binding