NEDD4L

Chr 18AD

NEDD4 like E3 ubiquitin protein ligase

Also known as: NEDD4-2, NEDD4.2, PVNH7, RSP5, hNEDD4-2

NCBI Gene: 23327 ENSG00000049759 UniProt: Q96PU5 OMIM: 606384

The protein is a HECT domain E3 ubiquitin ligase that transfers ubiquitin to target proteins for lysosomal degradation and critically regulates epithelial sodium channel (ENaC) cell surface expression to control epithelial sodium transport. Mutations cause periventricular nodular heterotopia 7, inherited in an autosomal dominant pattern. The pathogenic mechanism involves loss of function, as evidenced by the gene's extreme intolerance to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Periventricular nodular heterotopia 7MIM #617201

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · periventricular nodular heterotopia 7 · AD · ClinGen 2021

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

120

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 6.75

OE 0.11 (0.06–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.73Z-score

OE missense 0.55 (0.51–0.61)

308 obs / 555.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.20)

0≤0.351.4

Missense OE?0.55 (0.51–0.61)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 7 / 66.3Missense obs/exp: 308 / 555.0Syn Z: 0.69

Background carrier burden — how many people carry a rare variant somewhere in NEDD4L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 33

1,545 rare PASS variants

Rare truncating (LoF)

1 in 1,200

165 rare PASS variants

Rare synonymous (reference)

1 in 43

736 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NEDD4L. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 39	1 in 1,200
South Asian	~43k	1 in 33	1 in 660
Remaining (unassigned)	~30k	1 in 29	1 in 1,300
European (Finnish)	~27k	1 in 98	1 in 1,300
Admixed American	~22k	1 in 39	1 in 620
African / African American	~21k	1 in 32	1 in 610
East Asian	~20k	1 in 48	1 in 470
Ashkenazi Jewish	~13k	1 in 190	1 in 730
Middle Eastern	~2,884	1 in 40	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 31 coding exons well covered in gnomAD exomes; exons 3, 12 poorly covered; exons 2, 4, 5, 7, 8 and 9 more marginal. Genomes: all 31.? see exons ↓