NECTIN4

Chr 1AR

nectin cell adhesion molecule 4

Also known as: EDSS1, LNIR, PRR4, PVRL4, nectin-4

NCBI Gene: 81607 ENSG00000143217 UniProt: Q96NY8 OMIM: 609607

This gene encodes a member of the nectin family. The encoded protein contains two immunoglobulin-like (Ig-like) C2-type domains and one Ig-like V-type domain. It is involved in cell adhesion through trans-homophilic and -heterophilic interactions. It is a single-pass type I membrane protein. The soluble form is produced by proteolytic cleavage at the cell surface by the metalloproteinase ADAM17/TACE. The secreted form is found in both breast tumor cell lines and breast tumor patients. Mutations in this gene are the cause of ectodermal dysplasia-syndactyly syndrome type 1, an autosomal recessive disorder. Alternatively spliced transcript variants have been found but the full-length nature of the variant has not been determined.[provided by RefSeq, Jan 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Ectodermal dysplasia-syndactyly syndrome 1MIM #613573

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Ectodermal dysplasia-syndactyly syndrome 1; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.835

Z-score 3.73

OE 0.17 (0.08–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.28Z-score

OE missense 0.80 (0.72–0.88)

248 obs / 311.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.08–0.39)

0≤0.351.4

Missense OE?0.80 (0.72–0.88)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 4 / 23.5Missense obs/exp: 248 / 311.5Syn Z: 0.14

Background carrier burden — how many people carry a rare variant somewhere in NECTIN4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 98

667 rare PASS variants

Rare truncating (LoF)

1 in 3,400

54 rare PASS variants

Rare synonymous (reference)

1 in 120

311 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NECTIN4. 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 110	1 in 2,900
South Asian	~43k	1 in 62	1 in 7,200
Remaining (unassigned)	~30k	1 in 83	1 in 4,300
European (Finnish)	~27k	1 in 210	≈ 1 in 5,700
Admixed American	~22k	1 in 110	1 in 860
African / African American	~21k	1 in 92	≈ 1 in 5,600
East Asian	~20k	1 in 100	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 930	none seen
Middle Eastern	~2,884	1 in 74	≈ 1 in 1,400

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): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓