EPHB4

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

Basic information

Region (hg38): 7:100802564-100827523

Previous symbols: [ "HTK" ]

Links

ENSG00000196411 ∙ NCBI:2050 ∙ OMIM:600011 ∙ HGNC:3395 ∙ Uniprot:P54760 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Capillary malformation-arteriovenous malformation 2	AD	Cardiovascular	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	Cardiovascular	27400125; 28687708; 28730721; 29444212

ClinVar

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

• Cardiovascular phenotype (329 variants)
• not provided (259 variants)
• Capillary malformation-arteriovenous malformation 2 (57 variants)
• Inborn genetic diseases (33 variants)
• EPHB4-related condition (16 variants)
• Lymphatic malformation 7 (12 variants)
• not specified (8 variants)
• Capillary malformation-arteriovenous malformation 2;Lymphatic malformation 7 (4 variants)
• EPHB4-related disorders (3 variants)
• Hereditary lymphedema type I (2 variants)
• Lymphatic malformation 7;Capillary malformation-arteriovenous malformation 2 (2 variants)
• See cases (2 variants)
• Capillary malformation-arteriovenous malformation syndrome (1 variants)
• Vein of Galen aneurysmal malformation (1 variants)
• Venous malformation (1 variants)
• Stroke 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			1	167	9	177
missense	3	15	187	62	5	272
nonsense	21	7	1			29
start loss	1					1
frameshift	15	8	1			24
inframe indel			1			1
splice donor/acceptor (+/-2bp)		5	1			6
splice region		2	6	7	1	16
non coding			2	12	42	56
Total	40	35	194	241	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)
7-100803456-G-A		EPHB4-related disorder	Likely benign (Nov 07, 2022)
7-100803468-T-C		Cardiovascular phenotype	Uncertain significance (Apr 22, 2022)
7-100803470-C-T		Cardiovascular phenotype	Benign/Likely benign (Mar 23, 2021)
7-100803471-G-A		Cardiovascular phenotype	Uncertain significance (Mar 09, 2021)
7-100803476-C-A		Cardiovascular phenotype	Benign (Dec 18, 2023)
7-100803476-C-T		Cardiovascular phenotype	Likely benign (May 20, 2019)
7-100803477-G-A		Cardiovascular phenotype • EPHB4-related disorder	Uncertain significance (Jun 08, 2023)
7-100803477-G-C		Cardiovascular phenotype	Likely benign (Oct 03, 2022)
7-100803494-C-T		Cardiovascular phenotype	Benign (Nov 27, 2023)
7-100803495-G-A		Cardiovascular phenotype	Conflicting classifications of pathogenicity (Jan 29, 2024)
7-100803502-C-T		Cardiovascular phenotype	Uncertain significance (Jul 12, 2021)
7-100803503-C-T		Cardiovascular phenotype	Likely benign (Dec 08, 2019)
7-100803509-G-A		Cardiovascular phenotype	Likely benign (May 11, 2023)
7-100803510-G-T		EPHB4-associated vascular malformation spectrum	Uncertain significance (Jan 05, 2024)
7-100803513-T-C		Cardiovascular phenotype	Uncertain significance (Jan 01, 2024)
7-100803515-G-A		Cardiovascular phenotype	Likely benign (Jan 28, 2021)
7-100803517-A-G		Cardiovascular phenotype	Uncertain significance (Oct 08, 2023)
7-100803532-C-T		Cardiovascular phenotype	Likely benign (Apr 20, 2023)
7-100803535-T-C		Cardiovascular phenotype	Uncertain significance (Oct 12, 2021)
7-100803548-C-A		Cardiovascular phenotype	Uncertain significance (Jan 01, 2024)
7-100803557-T-C		Cardiovascular phenotype	Likely benign (Mar 07, 2024)
7-100803561-G-A			Benign/Likely benign (Jan 12, 2024)
7-100803563-CAG-C		Lymphatic malformation 7	Likely pathogenic (Apr 12, 2018)
7-100803574-C-T		Cardiovascular phenotype	Uncertain significance (Jan 16, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EPHB4	protein_coding	protein_coding	ENST00000358173	17	24935

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0135	0.987	125724	0	24	125748	0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.30	475	638	0.744	0.0000437	6241
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000294	0.000294
Ashkenazi Jewish	0.000499	0.000496
East Asian	0.0000545	0.0000544
Finnish	0.000105	0.0000924
European (Non-Finnish)	0.0000444	0.0000439
Middle Eastern	0.0000545	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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