EPS8

epidermal growth factor receptor pathway substrate 8

Basic information

Region (hg38): 12:15620134-15882329

Links

ENSG00000151491 ∙ NCBI:2059 ∙ OMIM:600206 ∙ HGNC:3420 ∙ Uniprot:Q12929 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive nonsyndromic hearing loss 102 (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 102 (Moderate), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 102 (Strong), mode of inheritance: AR
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 102 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 102	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic	24741995

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EPS8 gene.

• not provided (4 variants)
• Autosomal recessive nonsyndromic hearing loss 102 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EPS8 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			2	51	6	59
missense			93	6	2	101
nonsense	2	1				3
start loss						0
frameshift	3					3
inframe indel						0
splice donor/acceptor (+/-2bp)		1	1			2
splice region			4	12	6	22
non coding				44	30	74
Total	5	2	96	101	38

Variants in EPS8

This is a list of pathogenic ClinVar variants found in the EPS8 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-15621268-A-G			Likely benign (Jul 01, 2018)
12-15621303-TACAA-T		EPS8-related disorder	Likely benign (Aug 24, 2021)
12-15621316-A-G			Likely benign (Jan 28, 2022)
12-15621317-T-C			Uncertain significance (May 09, 2023)
12-15621331-C-T			Uncertain significance (Jul 05, 2022)
12-15621359-A-G			Likely benign (Aug 06, 2022)
12-15621360-C-T		Inborn genetic diseases	Uncertain significance (Dec 27, 2023)
12-15621387-C-T		Inborn genetic diseases	Uncertain significance (Aug 28, 2023)
12-15621412-C-T			Uncertain significance (Jul 05, 2022)
12-15622852-C-A			Benign (Apr 09, 2019)
12-15623161-C-T		not specified	Benign (Jan 30, 2024)
12-15623163-A-G			Likely benign (Nov 29, 2023)
12-15623192-T-C			Uncertain significance (Nov 14, 2023)
12-15623200-C-T		not specified	Likely benign (Aug 10, 2023)
12-15623221-C-A		Inborn genetic diseases	Uncertain significance (Jun 16, 2023)
12-15623230-A-C		not specified	Benign (Dec 15, 2023)
12-15623237-T-C		Inborn genetic diseases	Uncertain significance (Feb 07, 2023)
12-15623261-T-C			Uncertain significance (Jun 07, 2022)
12-15623264-A-G			Uncertain significance (Apr 09, 2023)
12-15623282-A-G			Uncertain significance (Feb 22, 2022)
12-15623283-C-T		not specified • EPS8-related disorder	Benign/Likely benign (Jan 19, 2024)
12-15623289-TA-T		not specified	Benign/Likely benign (May 07, 2018)
12-15623289-T-TA		not specified	Benign (Jan 30, 2024)
12-15623998-T-G			Likely benign (Jan 25, 2019)
12-15624003-A-G			Likely benign (Dec 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EPS8	protein_coding	protein_coding	ENST00000281172	20	262172

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.973	0.0269	125727	0	21	125748	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.811	402	450	0.892	0.0000239	5417
Missense in Polyphen		115	157.45	0.73039		1986
Synonymous	0.484	151	159	0.951	0.00000875	1539
Loss of Function	5.23	8	46.4	0.172	0.00000248	534

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000178	0.000178
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000881	0.0000879
Middle Eastern	0.000164	0.000163
South Asian	0.0000982	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture. Depending on its association with other signal transducers, can regulate different processes. Together with SOS1 and ABI1, forms a trimeric complex that participates in transduction of signals from Ras to Rac by activating the Rac- specific guanine nucleotide exchange factor (GEF) activity. Acts as a direct regulator of actin dynamics by binding actin filaments and has both barbed-end actin filament capping and actin bundling activities depending on the context. Displays barbed-end actin capping activity when associated with ABI1, thereby regulating actin-based motility process: capping activity is auto-inhibited and inhibition is relieved upon ABI1 interaction. Also shows actin bundling activity when associated with BAIAP2, enhancing BAIAP2- dependent membrane extensions and promoting filopodial protrusions. Involved in the regulation of processes such as axonal filopodia growth, stereocilia length, dendritic cell migration and cancer cell migration and invasion. Acts as a regulator of axonal filopodia formation in neurons: in the absence of neurotrophic factors, negatively regulates axonal filopodia formation via actin-capping activity. In contrast, it is phosphorylated in the presence of BDNF leading to inhibition of its actin-capping activity and stimulation of filopodia formation. Component of a complex with WHRN and MYO15A that localizes at stereocilia tips and is required for elongation of the stereocilia actin core. Indirectly involved in cell cycle progression; its degradation following ubiquitination being required during G2 phase to promote cell shape changes. {ECO:0000269|PubMed:15558031, ECO:0000269|PubMed:17115031}.
• Disease: DISEASE: Deafness, autosomal recessive, 102 (DFNB102) [MIM:615974]: A form of non-syndromic deafness characterized by profound hearing loss affecting all frequencies. Vestibular function is unaffected. {ECO:0000269|PubMed:24741995}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in EPS8 are associated with some cancers, such as pancreatic, oral squamous cell carcinomas or pituitary cancers. Contributes to cell transformation in response to growth factor treatment and is overexpressed in a number of tumors, indicating that EPS8 levels must be tightly regulated. {ECO:0000269|PubMed:11244499, ECO:0000269|PubMed:18566210, ECO:0000269|PubMed:19008210, ECO:0000269|PubMed:19116338, ECO:0000269|PubMed:19448673}.
• Pathway: EGF-EGFR Signaling Pathway;EGFR1;Regulation of RAC1 activity;ErbB1 downstream signaling;CDC42 signaling events;PDGFR-beta signaling pathway (Consensus)

Recessive Scores

• pRec: 0.299

Intolerance Scores

• rvis_EVS: -0.3
• rvis_percentile_EVS: 32.25

Haploinsufficiency Scores

• pHI: 0.173
• hipred: Y
• hipred_score: 0.790
• ghis: 0.542

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.871

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Eps8
• Phenotype: cellular 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); hearing/vestibular/ear phenotype; normal phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: signal transduction;epidermal growth factor receptor signaling pathway;Rho protein signal transduction;cell population proliferation;adult locomotory behavior;regulation of cell shape;positive regulation of signal transduction;exit from mitosis;Rac protein signal transduction;regulation of actin filament length;actin cytoskeleton reorganization;regulation of Rho protein signal transduction;dendritic cell migration;behavioral response to ethanol;barbed-end actin filament capping;actin filament bundle assembly;actin crosslink formation;actin polymerization-dependent cell motility;regulation of postsynaptic membrane neurotransmitter receptor levels;positive regulation of ruffle assembly;cellular response to leukemia inhibitory factor
• Cellular component: plasma membrane;brush border;cell cortex;postsynaptic density;NMDA selective glutamate receptor complex;cell junction;growth cone;vesicle;stereocilium;stereocilium tip;ruffle membrane;extracellular exosome;glutamatergic synapse
• Molecular function: actin binding;SH3/SH2 adaptor activity;protein binding;Rac guanyl-nucleotide exchange factor activity;Rac GTPase binding