EYA4

protein-coding

EYA transcriptional coactivator and phosphatase 4, the group of EYA transcriptional coactivator and phosphatases

Gene summary

This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may act as a transcriptional activator through its protein phosphatase activity, and it may be important for eye development, and for continued function of the mature organ of Corti. Mutations in this gene are associated with postlingual, progressive, autosomal dominant hearing loss at the deafness, autosomal dominant non-syndromic sensorineural 10 locus. The encoded protein is also a putative oncogene that mediates DNA repair, apoptosis, and innate immunity following DNA damage, cellular damage, and viral attack. Defects in this gene are also associated with dilated cardiomyopathy 1J. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

Previous symbols:

DFNA10
CMD1J

MANE transcript

NM_004100.5

Inheritance

ClinVar variants

P:103U:561B:234

Top phenotype

Cardiomyopathy, dilated, 1J

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr6:133,240,514-133,532,128

External References & Databases

Ensembl (ENSG00000112319)

Transcript & Mutation Effects

hg38 • Region Span ~291.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The EYA4 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/28/2017. This association was made using case-level data only. At least 7 variants (missense, nonsense, frameshift) have been reported in humans. EYA4 was first associated with this disease in humans as early as 2001 (Wayne et al.). Association is seen in at least 7 probands in 6 publications (11159937, 17568404, 25681523, 25963406, 25242383, 26331839). Variants in this gene segregated with disease in >70 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, at least one patient and a zebrafish model have been reported with a cardiac phenotype (Schonberger et al. 2005, 15735644). This gene-disease association is supported by a mouse model and expression studies. In summary, EYA4 is definitively associated with autosomal dominant nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/2018.

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011031

Submitter: Labcorp Genetics (formerly Invitae)

dilated cardiomyopathy 1JSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011541

Submitter: Orphanet

familial dilated cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

dilated cardiomyopathy 1JMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011541

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 10DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011031

Submitter: G2P

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

dilated cardiomyopathy 1JLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011541

Submitter: ClinGen

EYA4 was originally curated for DCM by the ClinGen GCEP on 11/08/2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 02/05/2025. As a result, the reclassification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. EYA4 was first reported in relation to autosomal dominant in 2000 (Schonberger et al, 2000, PMID: 10769282). Human genetic evidence supporting this gene-disease relationship includes case-level and segregation data. Of note, EYA4-related DCM has been observed with accompanying sensorineural hearing loss. At least 1 unique variant has been reported in humans (Schonberger et al, 2000, PMID: 10769282). This variant segregated with disease in 9 additional family members. This gene-disease association is supported by expression studies and studies in a non-human model organism (Schonberger et al, 2005, PMID: 15735644). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of EYA4 with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 02/05/2025 (SOP Version 10).

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 1JAD

Manifestation: Audiologic/Otolaryngologic; Cardiovascular

Intervention: Cardiovascular

Rationale: Related to cardiomyopathy, preventive measures and medical management may be helpful to help decrease morbidity

Comments: The condition may also include childhood-onset sensorineural hearing loss

Refs: 10769282; 10982027; 11159937; 15735644; 17568404; 17567890

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EYA4 variants in ClinVar

17 Conditions Cataloged

Dilated cardiomyopathy 1JTotal: 835

Cardiovascular phenotypeTotal: 410

not providedTotal: 247

not specifiedTotal: 91

Autosomal dominant nonsyndromic hearing loss 10Total: 89

EYA4-related disorderTotal: 51

Rare genetic deafnessTotal: 3

Hearing impairmentTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004100.5. 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			8 clinvar	217 clinvar	1 clinvar	226
missense	1 clinvar	3 clinvar	540 clinvar	15 clinvar	1 clinvar	560
nonsense	18 clinvar	18 clinvar	2 clinvar			38
start loss			2 clinvar			2
frameshift	27 clinvar	13 clinvar	2 clinvar			42
splice donor/acceptor (+/-2bp)	5 clinvar	18 clinvar	7 clinvar			30
Total	51	52	561	232	2	898

Highest pathogenic variant AF is 0.000026679505

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004100.5	RefSeq	NP_004091.3	19	MANE Select
ENST00000355286.12	Ensembl	ENSP00000347434.7	19	MANE Select
NM_001301012.2	RefSeq	NP_001287941.1	17	Standard
NM_001301013.2	RefSeq	NP_001287942.1	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
eya4	Danio rerio	Structure: pillar of the posterior semicircular canal Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

eya4

Danio rerio

Structure: pillar of the posterior semicircular canal

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

DNA Repair
DNA Double-Strand Break Repair
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
DNA Double Strand Break Response

Biological Process

DNA repair
multicellular organism development
visual perception
sensory perception of sound
anatomical structure morphogenesis

Molecular Function

protein tyrosine phosphatase activity
protein binding
metal ion binding

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367895
Coding exons: 19
Length: 291523
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125747
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.12	276	333	0.828	0.0000168	4153
Missense (PolyPhen)		92	135.82	0.67738		1741
Synonymous	1.38	103	122	0.841	0.00000668	1223
Loss of Function	4.18	10	37.7	0.265	0.00000173	467

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. May be involved in development of the eye (By similarity). {ECO:0000250|UniProtKB:Q99502}.;
Disease: DISEASE: Cardiomyopathy, dilated 1J (CMD1J) [MIM:605362]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD1J is characterized by the association of sensorineural hearing loss and dilated cardiomyopathy in the absence of other anomalies. {ECO:0000269|PubMed:15735644}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.0973
RVIS EVS: -0.42
RVIS percentile EVS: 25.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.269

Gene Damage Prediction

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