NEDD4L

NEDD4 like E3 ubiquitin protein ligase, the group of HECT domain containing|C2 domain containing

Basic information

Region (hg38): 18:58044225-58401540

Links

ENSG00000049759 ∙ NCBI:23327 ∙ OMIM:606384 ∙ HGNC:7728 ∙ Uniprot:Q96PU5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• periventricular nodular heterotopia (Supportive), mode of inheritance: AD
• periventricular nodular heterotopia 7 (Strong), mode of inheritance: AD
• periventricular nodular heterotopia 7 (Strong), mode of inheritance: AD
• periventricular nodular heterotopia 7 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Periventricular nodular heterotopia 7	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	27694961

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NEDD4L gene.

• not provided (790 variants)
• Periventricular nodular heterotopia 7 (90 variants)
• Inborn genetic diseases (26 variants)
• NEDD4L-related condition (6 variants)
• Intellectual disability (4 variants)
• not specified (3 variants)
• Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay (2 variants)
• Primary dilated cardiomyopathy (1 variants)
• Developmental disorder (1 variants)
• Autism spectrum disorder (1 variants)
• See cases (1 variants)
• Normal pregnancy (1 variants)
• Chromosome 5Q14.3 deletion syndrome, distal (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NEDD4L 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			3	136	14	153
missense		2	215	44	37	298
nonsense		1				1
start loss			1			1
frameshift			4	2		6
inframe indel			2	2		4
splice donor/acceptor (+/-2bp)			4	2		6
splice region		1	19	41	10	71
non coding			9	179	86	274
Total	0	3	238	365	137

Variants in NEDD4L

This is a list of pathogenic ClinVar variants found in the NEDD4L region.

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

Position	Type	Phenotype	Significance	ClinVar
18-58044386-T-G			Benign (Jul 06, 2018)
18-58044434-C-T			Benign (Jul 27, 2018)
18-58044615-C-T			Benign (May 21, 2021)
18-58044635-C-T			Benign (Jul 21, 2018)
18-58044662-T-C			Uncertain significance (Aug 29, 2023)
18-58044666-G-A			Likely benign (Oct 31, 2023)
18-58044671-G-T		Inborn genetic diseases	Uncertain significance (Jan 04, 2022)
18-58044673-C-T			Likely benign (Feb 01, 2024)
18-58044675-C-T			Likely benign (Jun 22, 2022)
18-58044681-G-T			Likely benign (Oct 13, 2023)
18-58044682-C-T			Uncertain significance (Oct 05, 2022)
18-58044683-C-T		Periventricular nodular heterotopia 7	Uncertain significance (Jan 30, 2020)
18-58044684-G-A			Likely benign (Aug 27, 2023)
18-58044687-C-T			Likely benign (Feb 11, 2022)
18-58044689-A-G			Uncertain significance (Jan 14, 2024)
18-58044698-C-G			Likely benign (Jan 06, 2022)
18-58044699-C-G			Likely benign (Apr 29, 2022)
18-58044699-C-T			Likely benign (Dec 09, 2023)
18-58044700-G-A			Uncertain significance (Jun 04, 2023)
18-58044702-A-G			Likely benign (Dec 02, 2022)
18-58044711-G-A			Uncertain significance (Feb 18, 2023)
18-58044713-G-A			Uncertain significance (Apr 08, 2021)
18-58044714-T-C			Uncertain significance (Sep 27, 2022)
18-58044715-G-A			Likely benign (May 16, 2022)
18-58044719-C-G		Periventricular nodular heterotopia 7	Likely benign (Jan 25, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NEDD4L	protein_coding	protein_coding	ENST00000400345	31	357174

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000315	124638	0	18	124656	0.0000722

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.73	308	555	0.555	0.0000321	6380
Missense in Polyphen		82	244.57	0.33528		3058
Synonymous	0.689	194	207	0.939	0.0000131	1781
Loss of Function	6.75	7	66.3	0.106	0.00000363	755

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000390	0.000390
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000556	0.0000556
Finnish	0.0000464	0.0000464
European (Non-Finnish)	0.0000363	0.0000354
Middle Eastern	0.0000556	0.0000556
South Asian	0.0000335	0.0000327
Other	0.00	0.00

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. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5 (PubMed:26363003, PubMed:27445338). Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Plays a role in dendrite formation by melanocytes (PubMed:23999003). Involved in the regulation of TOR signaling (PubMed:27694961). Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338). {ECO:0000250|UniProtKB:Q8CFI0, ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15217910, ECO:0000269|PubMed:15489223, ECO:0000269|PubMed:15496141, ECO:0000269|PubMed:15576372, ECO:0000269|PubMed:19144635, ECO:0000269|PubMed:23999003, ECO:0000269|PubMed:25631046, ECO:0000269|PubMed:26363003, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27694961}.
• Disease: DISEASE: Periventricular nodular heterotopia 7 (PVNH7) [MIM:617201]: A form of periventricular nodular heterotopia, a disorder resulting from a defect in the pattern of neuronal migration in which ectopic collections of neurons lie along the lateral ventricles of the brain or just beneath, contiguously or in isolated patches. PVNH7 is an autosomal dominant disease characterized by delayed psychomotor development, intellectual disability, and seizures in some patients. Additional features include cleft palate and toe syndactyly. {ECO:0000269|PubMed:27694961}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Endocytosis - Homo sapiens (human);Tight junction - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);Aldosterone-regulated sodium reabsorption - Homo sapiens (human);Diuretics Pathway, Pharmacodynamics;TGF-Ncore;TGF-beta Signaling Pathway;Disease;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Stimuli-sensing channels;Ion channel transport;Budding and maturation of HIV virion;Late Phase of HIV Life Cycle;HIV Life Cycle;HIV Infection;protein ubiquitylation;RNA Polymerase II Transcription;Infectious disease;Immune System;Adaptive Immune System;p73 transcription factor network;Downregulation of SMAD2/3:SMAD4 transcriptional activity;Antigen processing: Ubiquitination & Proteasome degradation;Transport of small molecules;Class I MHC mediated antigen processing & presentation;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;Signaling by TGF-beta Receptor Complex;Signaling by TGF-beta family members;Downregulation of TGF-beta receptor signaling;TGF-beta receptor signaling activates SMADs;Neurotrophic factor-mediated Trk receptor signaling;TGF-beta receptor signaling (Consensus)

Recessive Scores

• pRec: 0.256

Intolerance Scores

• loftool: 0.566
• rvis_EVS: -1.2
• rvis_percentile_EVS: 5.79

Haploinsufficiency Scores

• pHI: 0.469
• hipred: Y
• hipred_score: 0.825
• ghis: 0.584

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nedd4l
• Phenotype: homeostasis/metabolism phenotype; muscle phenotype; renal/urinary system phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; hearing/vestibular/ear 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); 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); hematopoietic system 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;protein polyubiquitination;regulation of membrane depolarization;ubiquitin-dependent protein catabolic process;protein monoubiquitination;sodium ion transport;cellular sodium ion homeostasis;excretion;response to metal ion;protein ubiquitination;viral life cycle;water homeostasis;regulation of protein stability;ion transmembrane transport;regulation of ion transmembrane transport;regulation of protein catabolic process;regulation of membrane potential;proteasome-mediated ubiquitin-dependent protein catabolic process;positive regulation of protein catabolic process;positive regulation of endocytosis;regulation of dendrite morphogenesis;regulation of membrane repolarization;protein K48-linked ubiquitination;ventricular cardiac muscle cell action potential;regulation of potassium ion transmembrane transporter activity;negative regulation of potassium ion transmembrane transporter activity;negative regulation of potassium ion transmembrane transport;negative regulation of sodium ion transmembrane transport;positive regulation of dendrite extension;negative regulation of protein localization to cell surface;negative regulation of sodium ion transmembrane transporter activity;positive regulation of caveolin-mediated endocytosis
• Cellular component: nucleoplasm;cytoplasm;multivesicular body;Golgi apparatus;cytosol;plasma membrane;extracellular exosome
• Molecular function: ubiquitin-protein transferase activity;protein binding;potassium channel regulator activity;sodium channel regulator activity;potassium channel inhibitor activity;sodium channel inhibitor activity;ion channel binding;ubiquitin protein ligase activity