EPHA4

protein-coding

EPH receptor A4, the group of EPH receptors|Sterile alpha motif domain containing

Gene summary

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin 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. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

Previous symbols:

TYRO1

MANE transcript

NM_004438.5

Inheritance

ClinVar variants

P:2U:158B:81

Top phenotype

EPHA4-related disorder

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr2:221,418,027-221,574,202

External References & Databases

Ensembl (ENSG00000116106)

Transcript & Mutation Effects

hg38 • Region Span ~156.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPHA4 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 222

not specifiedTotal: 79

EPHA4-related disorderTotal: 2

Epileptic encephalopathyTotal: 1

atypical cerebral palsyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004438.5. 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			2 clinvar	66 clinvar	9 clinvar	77
missense		1 clinvar	151 clinvar	4 clinvar	2 clinvar	158
nonsense			2 clinvar			2
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	2	158	70	11	241

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004438.5	RefSeq	NP_004429.1	17	MANE Select
ENST00000281821.7	Ensembl	ENSP00000281821.2	17	MANE Select
NM_001304536.2	RefSeq	NP_001291465.1	17	Standard
NM_001304537.2	RefSeq	NP_001291466.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Spinal Cord Injury
Gene regulatory network modelling somitogenesis
Developmental Biology
EPH-Ephrin signaling

Biological Process

cell adhesion
transmembrane receptor protein tyrosine kinase signaling pathway
axon guidance
adult walking behavior
motor neuron axon guidance

Molecular Function

amyloid-beta binding
protein kinase activity
transmembrane receptor protein tyrosine kinase activity
GPI-linked ephrin receptor activity
transmembrane-ephrin receptor activity

Cellular Component

cytoplasm
mitochondrial outer membrane
endoplasmic reticulum
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281821
Coding exons: 17
Length: 156176
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.89	377	571	0.660	0.0000322	6485
Missense (PolyPhen)		199	322.91	0.61627		3695
Synonymous	-0.194	219	215	1.02	0.0000126	1912
Loss of Function	6.18	4	52.2	0.0767	0.00000326	555

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor tyrosine kinase which binds membrane-bound ephrin 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. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium. {ECO:0000269|PubMed:17143272}.;

Recessive Scores

pRec: 0.219

Intolerance Scores

LoFtool: 0.118
RVIS EVS: -1.4
RVIS percentile EVS: 4.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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