EPHA4

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

Basic information

Region (hg38): 2:221418026-221574202

Previous symbols: [ "TYRO1" ]

Links

ENSG00000116106 ∙ NCBI:2043 ∙ OMIM:602188 ∙ HGNC:3388 ∙ Uniprot:P54764 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (Disputed Evidence), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EPHA4 gene.

• not provided (141 variants)
• Inborn genetic diseases (24 variants)
• Epileptic encephalopathy (1 variants)
• atypical cerebral palsy (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EPHA4 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				46	11	57
missense		1	66	2	1	70
nonsense						0
start loss						0
frameshift		1	1			2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1	4		5
non coding				20	5	25
Total	0	2	67	68	17

Variants in EPHA4

This is a list of pathogenic ClinVar variants found in the EPHA4 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-221426029-C-G			Uncertain significance (Apr 04, 2024)
2-221426033-C-T		EPHA4-related disorder • not specified	Conflicting classifications of pathogenicity (Jan 19, 2024)
2-221426039-C-G			Uncertain significance (Aug 24, 2023)
2-221426047-C-A		not specified	Uncertain significance (Aug 11, 2022)
2-221426068-G-A			Uncertain significance (May 22, 2023)
2-221426072-G-A			Uncertain significance (Sep 08, 2023)
2-221426074-A-G			Uncertain significance (Nov 19, 2023)
2-221426097-C-T			Benign (Jul 31, 2021)
2-221426109-C-T			Benign (Jan 29, 2024)
2-221426112-G-T			Likely benign (Nov 27, 2023)
2-221426114-T-C			Uncertain significance (May 13, 2023)
2-221426131-C-G			Uncertain significance (Nov 03, 2022)
2-221426150-T-C			Likely benign (Dec 31, 2022)
2-221426155-C-T			Likely benign (Sep 26, 2023)
2-221426156-G-A			Likely benign (Nov 27, 2023)
2-221426474-C-T		not specified	Conflicting classifications of pathogenicity (Nov 21, 2023)
2-221426475-G-A			Likely benign (Jun 15, 2023)
2-221426475-G-T			Uncertain significance (May 16, 2021)
2-221426516-A-G			Uncertain significance (Jul 31, 2023)
2-221426527-T-C			Uncertain significance (Jun 28, 2022)
2-221426537-T-C		not specified	Uncertain significance (Jan 26, 2022)
2-221426559-G-A			Likely benign (Mar 03, 2023)
2-221426564-C-T		not specified	Uncertain significance (Jan 04, 2024)
2-221426576-CA-C			Uncertain significance (Sep 01, 2022)
2-221426597-G-T		not specified	Uncertain significance (Nov 09, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EPHA4	protein_coding	protein_coding	ENST00000281821	17	156176

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000438	125730	0	18	125748	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.89	377	571	0.660	0.0000322	6485
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000418	0.000416
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.0000528	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Axon guidance - Homo sapiens (human);Spinal Cord Injury;Gene regulatory network modelling somitogenesis;Developmental Biology;EPH-Ephrin signaling;EGFR1;Axon guidance;EPHA forward signaling (Consensus)

Recessive Scores

• pRec: 0.219

Intolerance Scores

• loftool: 0.118
• rvis_EVS: -1.4
• rvis_percentile_EVS: 4.22

Haploinsufficiency Scores

• pHI: 0.772
• hipred: Y
• hipred_score: 0.846
• ghis: 0.601

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Epha4
• Phenotype: endocrine/exocrine gland phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; normal phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: cell adhesion;transmembrane receptor protein tyrosine kinase signaling pathway;axon guidance;adult walking behavior;motor neuron axon guidance;glial cell migration;negative regulation of neuron projection development;peptidyl-tyrosine phosphorylation;corticospinal tract morphogenesis;regulation of GTPase activity;positive regulation of JUN kinase activity;protein autophosphorylation;ephrin receptor signaling pathway;negative regulation of axon regeneration;regulation of astrocyte differentiation;regulation of axonogenesis;positive regulation of dendrite morphogenesis;protein stabilization;regulation of dendritic spine morphogenesis;positive regulation of protein tyrosine kinase activity;nephric duct morphogenesis;fasciculation of sensory neuron axon;fasciculation of motor neuron axon;neuron projection guidance;synapse pruning;neuron projection fasciculation;negative regulation of long-term synaptic potentiation;positive regulation of amyloid-beta formation;positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process;negative regulation of proteolysis involved in cellular protein catabolic process;cellular response to amyloid-beta;regulation of modification of synaptic structure;positive regulation of Rho guanyl-nucleotide exchange factor activity
• Cellular component: cytoplasm;mitochondrial outer membrane;endoplasmic reticulum;Golgi apparatus;plasma membrane;integral component of plasma membrane;cell surface;postsynaptic density;cell junction;filopodium;axon;dendrite;neuromuscular junction;early endosome membrane;neuron projection;dendritic spine;dendritic shaft;perikaryon;receptor complex;axon terminus;axonal growth cone;Schaffer collateral - CA1 synapse;glutamatergic synapse;integral component of postsynaptic membrane;integral component of presynaptic membrane
• Molecular function: amyloid-beta binding;protein kinase activity;transmembrane receptor protein tyrosine kinase activity;GPI-linked ephrin receptor activity;transmembrane-ephrin receptor activity;protein binding;ATP binding;kinase activity;PH domain binding;identical protein binding;ephrin receptor binding;DH domain binding;protein tyrosine kinase binding