EPHB4

EPH receptor B4, the group of Sterile alpha motif domain containing|EPH receptors

Basic information

Region (hg38): 7:100802565-100827523

Previous symbols: [ "HTK" ]

Links

ENSG00000196411NCBI:2050OMIM:600011HGNC:3395Uniprot:P54760AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • capillary malformation-arteriovenous malformation 2 (Limited), mode of inheritance: AD
  • capillary malformation-arteriovenous malformation 2 (Strong), mode of inheritance: AD
  • capillary malformation-arteriovenous malformation 2 (Definitive), mode of inheritance: AD
  • lymphatic malformation 7 (Limited), mode of inheritance: AD
  • capillary malformation-arteriovenous malformation syndrome (Supportive), mode of inheritance: AD
  • capillary malformation-arteriovenous malformation 2 (Strong), mode of inheritance: AD
  • lymphatic malformation 7 (Strong), mode of inheritance: AD
  • EPHB4-associated vascular malformation spectrum (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Capillary malformation-arteriovenous malformation 2ADCardiovascularLife-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/mortalityCardiovascular27400125; 28687708; 28730721; 29444212

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EPHB4 gene.

  • not provided (36 variants)
  • Capillary malformation-arteriovenous malformation 2 (7 variants)
  • Cardiovascular phenotype (4 variants)
  • Capillary malformation-arteriovenous malformation syndrome (2 variants)
  • Hereditary lymphedema type I (1 variants)
  • Lymphatic malformation 7 (1 variants)
  • EPHB4-related disorder (1 variants)
  • Arteriovenous malformation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EPHB4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
183
clinvar
9
clinvar
192
missense
3
clinvar
15
clinvar
241
clinvar
62
clinvar
4
clinvar
325
nonsense
25
clinvar
9
clinvar
1
clinvar
35
start loss
1
clinvar
1
frameshift
20
clinvar
10
clinvar
1
clinvar
31
inframe indel
1
clinvar
1
splice donor/acceptor (+/-2bp)
7
clinvar
1
clinvar
8
splice region
2
6
11
1
20
non coding
4
clinvar
22
clinvar
43
clinvar
69
Total 49 41 249 267 56

Highest pathogenic variant AF is 0.00000657

Variants in EPHB4

This is a list of pathogenic ClinVar variants found in the EPHB4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
7-100803321-GTC-G Benign (May 26, 2021)1282284
7-100803456-G-A EPHB4-related disorder Likely benign (Nov 07, 2022)3029263
7-100803468-T-C Cardiovascular phenotype Uncertain significance (Apr 22, 2022)2217994
7-100803470-C-T Cardiovascular phenotype Benign/Likely benign (Mar 23, 2021)1578559
7-100803471-G-A Cardiovascular phenotype Uncertain significance (Mar 09, 2021)1798092
7-100803476-C-A Cardiovascular phenotype Benign (Dec 18, 2023)811022
7-100803476-C-T Cardiovascular phenotype Likely benign (May 20, 2019)1798004
7-100803477-G-A Cardiovascular phenotype • EPHB4-related disorder Uncertain significance (Jun 08, 2023)1797991
7-100803477-G-C Cardiovascular phenotype Likely benign (Oct 03, 2022)1797989
7-100803494-C-T Cardiovascular phenotype Benign (Nov 27, 2023)1797826
7-100803495-G-A Cardiovascular phenotype Conflicting classifications of pathogenicity (Jan 29, 2024)1450144
7-100803502-C-T Cardiovascular phenotype Uncertain significance (Jul 12, 2021)1797736
7-100803503-C-T Cardiovascular phenotype Likely benign (Dec 08, 2019)1797727
7-100803509-G-A Cardiovascular phenotype Likely benign (May 11, 2023)2565153
7-100803510-G-T EPHB4-associated vascular malformation spectrum Uncertain significance (Jan 05, 2024)3068705
7-100803513-T-C Cardiovascular phenotype Uncertain significance (Jan 01, 2024)3224288
7-100803515-G-A Cardiovascular phenotype Likely benign (Jan 28, 2021)1797578
7-100803517-A-G Cardiovascular phenotype Uncertain significance (Oct 08, 2023)3224287
7-100803532-C-T Cardiovascular phenotype Likely benign (Apr 20, 2023)2539546
7-100803535-T-C Cardiovascular phenotype Uncertain significance (Oct 12, 2021)1797299
7-100803548-C-A Cardiovascular phenotype Uncertain significance (Jan 01, 2024)3224286
7-100803557-T-C Cardiovascular phenotype Likely benign (Mar 07, 2024)3224285
7-100803561-G-A Benign/Likely benign (Jan 12, 2024)2701266
7-100803563-CAG-C Lymphatic malformation 7 Likely pathogenic (Apr 12, 2018)692019
7-100803574-C-T Cardiovascular phenotype Uncertain significance (Jan 16, 2024)3224284

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
EPHB4protein_codingprotein_codingENST00000358173 1724935
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.01350.9871257240241257480.0000954
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense2.304756380.7440.00004376241
Missense in Polyphen178301.110.591153021
Synonymous-1.023032811.080.00002072073
Loss of Function4.871451.80.2700.00000308500

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0002940.000294
Ashkenazi Jewish0.0004990.000496
East Asian0.00005450.0000544
Finnish0.0001050.0000924
European (Non-Finnish)0.00004440.0000439
Middle Eastern0.00005450.0000544
South Asian0.00003270.0000327
Other0.000.00

dbNSFP

Source: dbNSFP

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.;
Pathway
Axon guidance - Homo sapiens (human);Vitamin D Receptor Pathway;Developmental Biology;EPH-Ephrin signaling;Ephrin signaling;EGFR1;Ephrin B reverse signaling;Axon guidance;EPHB forward signaling (Consensus)

Recessive Scores

pRec
0.258

Intolerance Scores

loftool
0.274
rvis_EVS
-1.5
rvis_percentile_EVS
3.6

Haploinsufficiency Scores

pHI
0.469
hipred
Y
hipred_score
0.694
ghis
0.638

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.876

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Ephb4
Phenotype
muscle phenotype; growth/size/body region phenotype; renal/urinary system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype;

Zebrafish Information Network

Gene name
ephb4b
Affected structure
heart tube
Phenotype tag
abnormal
Phenotype quality
decreased occurrence

Gene ontology

Biological process
angiogenesis;cell migration involved in sprouting angiogenesis;heart morphogenesis;cell adhesion;transmembrane receptor protein tyrosine kinase signaling pathway;axon guidance;peptidyl-tyrosine phosphorylation;protein autophosphorylation;ephrin receptor signaling pathway
Cellular component
extracellular region;cytosol;plasma membrane;integral component of plasma membrane;neuron projection;receptor complex;extracellular exosome
Molecular function
protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;ephrin receptor activity;transmembrane-ephrin receptor activity;protein binding;ATP binding