NECTIN1
protein-codingnectin cell adhesion molecule 1, the group of Nectins and nectin-like molecules|V-set domain containing|CD molecules|C2-set domain containing
Gene summary
This gene encodes an adhesion protein that plays a role in the organization of adherens junctions and tight junctions in epithelial and endothelial cells. The protein is a calcium(2+)-independent cell-cell adhesion molecule that belongs to the immunoglobulin superfamily and has 3 extracellular immunoglobulin-like loops, a single transmembrane domain (in some isoforms), and a cytoplasmic region. This protein acts as a receptor for glycoprotein D (gD) of herpes simplex viruses 1 and 2 (HSV-1, HSV-2), and pseudorabies virus (PRV) and mediates viral entry into epithelial and neuronal cells. Mutations in this gene cause cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1) as well as non-syndromic cleft lip with or without cleft palate (CL/P). Alternative splicing results in multiple transcript variants encoding proteins with distinct C-termini. [provided by RefSeq, Oct 2009]
- HVEC
- ED4
- PVRL1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~105.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009151
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009151
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009151
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009151
Submitter: ClinGen
The *NECTIN1* gene is located at chromosome 11q23.3, and encodes an adhesion protein that plays a role in the organization of adherens and tight junctions in epithelial and endothelial cells. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: Cleft lip/palate-ectodermal dysplasia syndrome (MIM:225060) and Orofacial cleft 7 (MIM:225060). Here, we curate autosomal recessive cleft lip/palate-ectodermal dysplasia syndrome (http://purl.obolibrary.org/obo/MONDO_0009151). *NECTIN1* was reported in connection with autosomal cleft lip/palate-ectodermal dysplasia syndrome in 2000 (Suzuki et al., 2000 PMID: 10932188). Five protein truncating mutations (3 nonsense, 2 frameshift) reported in three publications have been included in this curation (PMIDs: 25913853, 10932188, 34556655). Molecular mechanism of pathogenicity appears to be loss-of-function whereby homozygous *NECTIN1* molecular defects are predicted to disrupt the protein-protein interactions needed to initiate the cell-cell adhesion process (PMID: 25913853). Parental consanguinity and the unique clinical features may differentiate this syndrome from other disease assertions, therefore the expert panel decided to not reduce the scores of probands with established or suspected consanguineous parents. The maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression studies, protein interaction, and a mouse model. In summary, there is definitive evidence supporting the relationship between *NECTIN1* and autosomal recessive cleft lip/palate-ectodermal dysplasia syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 06/20/2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0009151
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009151
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dermatologic; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NECTIN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002855.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 50 | 1 | 55 | ||
| missense | 37 | 7 | 44 | |||
| nonsense | 3 | 3 | 6 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 5 | 4 | 45 | 57 | 1 | 112 |
Highest pathogenic variant AF is 0.000011157781
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002846.3 | 6 | MANE Select | |
| Ensembl | ENSP00000264025.3 | 6 | MANE Select | |
| RefSeq | NP_976030.1 | 8 | Standard | |
| RefSeq | NP_976031.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Adherens junction - Homo sapiens (human)
- Herpes simplex infection - Homo sapiens (human)
- EGFR1
- Cell-cell junction organization
Biological Process
- lens morphogenesis in camera-type eye
- desmosome organization
- iron ion transport
- immune response
- cell adhesion
Molecular Function
- virus receptor activity
- protein binding
- coreceptor activity
- carbohydrate binding
- signaling receptor activity
Cellular Component
- extracellular region
- plasma membrane
- adherens junction
- cell-cell adherens junction
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264025
- Coding exons
- 6
- Length
- 105675
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125748
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.28 | 270 | 336 | 0.803 | 0.0000228 | 3350 |
| Missense (PolyPhen) | 82 | 120.76 | 0.67902 | 1282 | ||
| Synonymous | 0.669 | 134 | 144 | 0.929 | 0.0000108 | 1057 |
| Loss of Function | 2.99 | 6 | 20.7 | 0.290 | 0.00000115 | 227 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000064 | 0.000062 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Promotes cell-cell contacts by forming homophilic or heterophilic trans-dimers. Heterophilic interactions have been detected between NECTIN1 and NECTIN3 and between NECTIN1 and NECTIN4. Has some neurite outgrowth-promoting activity. {ECO:0000269|PubMed:21980294}.;
- Disease
- DISEASE: Ectodermal dysplasia, Margarita Island type (EDMI) [MIM:225060]: An autosomal recessive form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is a syndrome characterized by the association of cleft lip/palate, ectodermal dysplasia (sparse short and dry scalp hair, sparse eyebrows and eyelashes), and partial syndactyly of the fingers and/or toes. Two thirds of the patients do not manifest oral cleft but present with abnormal teeth and nails. {ECO:0000269|PubMed:10932188}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Non-syndromic orofacial cleft 7 (OFC7) [MIM:225060]: A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. {ECO:0000269|PubMed:10932188}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.246
Intolerance Scores
- RVIS EVS
- -0.24
- RVIS percentile EVS
- 36.31
Essentials
- Essential (gene trap)
- N