EPHB4
protein-codingEPH receptor B4, the group of Sterile alpha motif domain containing|EPH receptors
Gene summary
Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development. [provided by RefSeq, Jul 2008]
- HTK
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~25.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700080
Submitter: ClinGen
Ephrin Receptor EphB4 (EPHB4; MIM#600011) is a receptor tyrosine kinase transmembrane protein that has a critical role in angiogenesis and vascular development. Regulation is complex with bidirectional signaling critical for vasculature assembly and mesenchymal cell differentiation. Autosomal dominant pathogenic variants in EPHB4 were first described in 2016 (PMID:28687708, 27400125) in association with variable vascular malformations including capillary and arteriovenous malformations (CM-AVM), and has since been described in many additional affected individuals with phenotypes including CM-AVMs, lymphatic malformations, non-immune hydrops fetalis, recurrent epistaxis and additional vascular and lymphatic phenotypes (PMID:33864021, 27400125, 29444212, others). The phenotype of EPHB4 has high intra- and interfamilial variability (PMID:33864021, 27400125) and can be associated with a spectrum of phenotypes ranging from subtle features of lymphatic dysfunction to lethal non-immune hydrops fetalis. The mechanism is loss of function, and while nonsense and frameshift variants are found throughout the coding sequence, pathogenic missense variants are found to be enriched within the Tyrosine Kinase domain (for Review; PMID:30819650) Animal models of EPHB4 demonstrate defects in vascular modeling, growth restriction, pre- and postnatal edemas, and tortuous dilated lymphatic vessels (PMID:10518221, 27400125, 29444212). EPHB4 is curated by the Prenatal Gene Curation Expert Panel as Definitive for EPHB4-associated vascular malformation spectrum.
Inheritance Pattern: AD
Disease ID:MONDO:0015009
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0020785
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0700080
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015009
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0700080
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020785
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0020785
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0020785
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Life-threatening complications of arteriovenous malformations and arteriovenous fistulas can include bleeding, congestive heart failure, and/or neurologic consequences, and surveillance may allow early detection and medical/surgical management, which may decrease morbidity/mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EPHB4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004444.5. 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 | 286 | 2 | 292 | ||
| missense | 5 | 33 | 455 | 128 | 621 | |
| nonsense | 24 | 23 | 2 | 49 | ||
| start loss | 1 | 1 | ||||
| frameshift | 40 | 25 | 4 | 69 | ||
| splice donor/acceptor (+/-2bp) | 3 | 16 | 7 | 26 | ||
| Total | 72 | 98 | 472 | 414 | 2 | 1058 |
Highest pathogenic variant AF is 0.0000065748814
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004435.3 | 17 | MANE Select | |
| Ensembl | ENSP00000350896.3 | 17 | MANE Select | |
| Ensembl | ENSP00000353833.3 | 16 | Standard | |
| Ensembl | ENSP00000353833.3 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ephb4b | Danio rerio | Structure: heart tube Quality: decreased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Axon guidance - Homo sapiens (human)
- Vitamin D Receptor Pathway
- Developmental Biology
- EPH-Ephrin signaling
- Ephrin signaling
Biological Process
- angiogenesis
- cell migration involved in sprouting angiogenesis
- heart morphogenesis
- cell adhesion
- transmembrane receptor protein tyrosine kinase signaling pathway
Molecular Function
- protein tyrosine kinase activity
- transmembrane receptor protein tyrosine kinase activity
- ephrin receptor activity
- transmembrane-ephrin receptor activity
- protein binding
Cellular Component
- extracellular region
- cytosol
- plasma membrane
- integral component of plasma membrane
- neuron projection
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000358173
- Coding exons
- 17
- Length
- 24935
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125748
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.30 | 475 | 638 | 0.744 | 0.0000437 | 6241 |
| Missense (PolyPhen) | 178 | 301.11 | 0.59115 | 3021 | ||
| Synonymous | -1.02 | 303 | 281 | 1.08 | 0.0000207 | 2073 |
| Loss of Function | 4.87 | 14 | 51.8 | 0.270 | 0.00000308 | 500 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00010 | 0.000092 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4- mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis. {ECO:0000269|PubMed:12734395, ECO:0000269|PubMed:16424904, ECO:0000269|PubMed:27400125}.;
- Disease
- DISEASE: Hydrops fetalis, non-immune, and/or atrial septal defect (HFASD) [MIM:617300]: A form of non-immune hydrops fetalis, a condition characterized by fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are non-immune conditions that present with generalized edema of the fetus. Approximately 15% of non-immune cases result from a lymphatic abnormality. HFASD is an autosomal dominant, lymphatic-related form with variable expressivity. Some patients suffer from severe manifestations that can result in early death, whereas others have milder clinical features, such as atrial septal defect or varicose veins as adults. The hydrops and/or swelling improves spontaneously in those who survive the neonatal period. {ECO:0000269|PubMed:27400125}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.258
Intolerance Scores
- LoFtool
- 0.274
- RVIS EVS
- -1.5
- RVIS percentile EVS
- 3.6
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.876
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |