GeneBe

NEDD4L

protein-coding

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

Gene summary

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_001144967.3

Inheritance

AD

ClinVar variants

P:9U:352B:357

Top phenotype

Periventricular nodular heterotopia 7

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr18:58,044,226-58,401,540

External References & Databases

Ensembl (ENSG00000049759)NCBI Gene (23327)OMIM (606384)HGNC:7728GenCCUniProt (Q96PU5)AlphaFoldClinVar (NEDD4L)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~357.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

periventricular nodular heterotopiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020341

Submitter: Orphanet

periventricular nodular heterotopia 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014966

Submitter: G2P

periventricular nodular heterotopia 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014966

Submitter: Ambry Genetics

periventricular nodular heterotopia 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014966

Submitter: Labcorp Genetics (formerly Invitae)

periventricular nodular heterotopia 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014966

Submitter: ClinGen

NEDD4L was first reported in relation to syndromic periventricular nodular heterotopia in 2016 (Broix et al., PMID 27694961). Evidence supporting this gene-disease relationship include case level data and experimental data. Variants in this gene have been reported in at least 15 probands in 5 publications, including at least 6 de novo missense variants (PMIDs: 27694961, 28515470, 30393983, 32117442, 34087865). To date, all reported cases have demonstrated periventricular nodular heterotopia and developmental delay; 13 of 15 probands demonstrated syndactyly, 8 demonstrated a cleft palate, and at least 5 demonstrated additional malformations of cortical development such as polymicrogyria. Recurrent variants are found in 11 of the reported cases (6 for one and 5 for the other). The mechanism of disease is dominant negative (PMID: 27694961). This gene-disease relationship is supported by animal models, in vitro studies of biochemical function, and cell culture assays using non-patient derived cells. More experimental evidence is available in the literature but not cited here, as a classification of definitive has been reached. In summary, NEDD4L is definitively associated with autosomal dominant periventricular nodular heterotopia 7. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 11/30/2021 (SOP Version 8).

periventricular nodular heterotopia 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014966

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Periventricular nodular heterotopia 7AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

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

Refs: 27694961Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEDD4L variants in ClinVar

14 Conditions Cataloged
not providedTotal: 1017
Periventricular nodular heterotopia 7Total: 109
Inborn genetic diseasesTotal: 90
not specifiedTotal: 37
NEDD4L-related disorderTotal: 34
Intellectual disabilityTotal: 4
Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delayTotal: 4
Chromosome 5Q14.3 deletion syndrome, distalTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001144967.3. 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.

EffectPLPVUSLBBSum
synonymous
10
clinvar
202
clinvar
12
clinvar
 224
missense
2
clinvar
5
clinvar
321
clinvar
92
clinvar
46
clinvar
 466
nonsense
1
clinvar
2
clinvar
1
clinvar
 4
start loss
1
clinvar
 1
frameshift
7
clinvar
2
clinvar
 9
splice donor/acceptor (+/-2bp)
1
clinvar
11
clinvar
2
clinvar
 14
Total2735229958718

Highest pathogenic variant AF is 0.000004811837

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 112 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001144967.3RefSeqNP_001138439.131MANE Select
ENST00000400345.8EnsemblENSP00000383199.231MANE Select
NM_001144964.1RefSeqNP_001138436.125Standard
NM_001144965.2RefSeqNP_001138437.125Standard

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)
  • Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
  • Diuretics Pathway, Pharmacodynamics

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • protein polyubiquitination
  • regulation of membrane depolarization
  • ubiquitin-dependent protein catabolic process
  • protein monoubiquitination

Molecular Function

  • ubiquitin-protein transferase activity
  • protein binding
  • potassium channel regulator activity
  • sodium channel regulator activity
  • potassium channel inhibitor activity

Cellular Component

  • nucleoplasm
  • cytoplasm
  • multivesicular body
  • Golgi apparatus
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000400345
Coding exons
31
Length
357174
Individuals with no LoFs
124638
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
124656
p
0.0000722
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.733085550.5550.00003216380
Missense (PolyPhen)82244.570.335283058
Synonymous0.6891942070.9390.00001311781
Loss of Function6.75766.30.1060.00000363755

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000130.00013rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish00.0absent
East Asian0.0000560.000056rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000360.000035rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.256

Intolerance Scores

LoFtool
0.566
RVIS EVS
-1.2
RVIS percentile EVS
5.79

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.973

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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