EPS8

protein-coding

epidermal growth factor receptor pathway substrate 8

Gene summary

This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004447.6

Inheritance

ClinVar variants

P:13U:220B:97

Top phenotype

Deafness, autosomal recessive 102

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr12:15,620,134-15,882,329

External References & Databases

Ensembl (ENSG00000151491)

Transcript & Mutation Effects

hg38 • Region Span ~262.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 102STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014428

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 102DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014428

Submitter: LiferaOmics

ClinGen GDR AR nonsyndromic hearing loss 102 -Moderate (approved 2020) Genetic evidence – Published:ClinGen scored Genetic evidence = 4.5/12 and Experimental evidence = 5.0/6 (overall 9.5/18). The primary publication used for the GDR was PMID: 24741995, with additional scored publications PMID: 27344577 and PMID: 30303587 Additional published cases not included in the original ClinGen scoring: PMID: 34637946 reports 1 proband with congenital profound sensorineural hearing loss and a homozygous canonical splice variant in EPS8. Case-level (biallelic predicted null in AR model; homozygous scored once; no consanguinity deduction applied as not specified) = 1.5; segregation = 0; case-control = 0. Contribution = 1.5 PMID: 36635257 reports 1 additional unrelated proband with biallelic pathogenic EPS8 variants and nonsyndromic sensorineural hearing loss. Case-level (biallelic predicted null in AR model; homozygous scored once; no consanguinity deduction applied as not specified) = 1.5; segregation = 0; case-control = 0. Contribution = 1.5 Published genetic evidence total = ClinGen 4.5 + 1.5 + 1.5 = 7.5/12 Genetic evidence – our case: 1 proband; homozygous canonical splice variant; autosomal recessive inheritance; parents consanguineous; no additional genotyped affected relatives; no segregation or case-control data. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation = 0; case-control = 0. Current case contribution = 1.0/12 Total genetic evidence (published + our case) = 8.5/12 Experimental evidence – Published: Per ClinGen Hearing Loss GCEP curation, EPS8 has strong hair-cell stereocilia biological relevance and a knockout mouse model demonstrating profound deafness and abnormal stereocilia morphology. Experimental evidence total (ClinGen-scored) = 5.0/6 Overall score = 13.5 First report: PMID: 24741995 (2014) Additional independent families published in subsequent years (2016, 2018, 2021, 2022)

autosomal recessive nonsyndromic hearing loss 102MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014428

Submitter: ClinGen

EPS8 was reported in relation to ARNSHL in 2014 (Behlouli et al., PMID: 24741995). At least 4 unique variants (nonsense, frameshift, missense, splicing) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMID: 24741995, 27344577, 30303587) and segregated with disease in 2 additional family members. This gene-disease association is supported by animal models, expression studies, protein interactions, and functional alterations in non-patient cells. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. An additional case was counted under case-level data for the genetic evidence for this gene-disease association. A proband with an affected sibling from a consanguineous family was found to harbor the NM_004447:c.1151C>T (p.Pro384Leu) variant. This would increase the genetic evidence score from 9.5 to 10 points and the overall classification would remain "Moderate." This classification was approved by the ClinGen Hearing Loss Working Group on 2/6/2020.

autosomal recessive nonsyndromic hearing loss 102MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014428

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 102STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014428

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 102AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 24741995

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPS8 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 273

Inborn genetic diseasesTotal: 135

not specifiedTotal: 49

EPS8-related disorderTotal: 42

Autosomal recessive nonsyndromic hearing loss 102Total: 19

DeafnessTotal: 2

Hearing loss, autosomal recessive 106Total: 1

Hearing loss, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004447.6. 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			3 clinvar	71 clinvar	3 clinvar	77
missense			204 clinvar	22 clinvar	1 clinvar	227
nonsense	4 clinvar	2 clinvar				6
start loss			2 clinvar			2
frameshift	3 clinvar					3
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	11 clinvar			15
Total	9	4	220	93	4	330

Highest pathogenic variant AF is 0.0000024791257

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 110 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004447.6	RefSeq	NP_004438.3	20	MANE Select
ENST00000281172.10	Ensembl	ENSP00000281172.5	20	MANE Select
NM_001413831.1	RefSeq	NP_001400760.1	21	Standard
NM_001413832.1	RefSeq	NP_001400761.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EGF-EGFR Signaling Pathway
EGFR1
Regulation of RAC1 activity
ErbB1 downstream signaling
CDC42 signaling events

Biological Process

signal transduction
epidermal growth factor receptor signaling pathway
Rho protein signal transduction
cell population proliferation
adult locomotory behavior

Molecular Function

actin binding
SH3/SH2 adaptor activity
protein binding
Rac guanyl-nucleotide exchange factor activity
Rac GTPase binding

Cellular Component

plasma membrane
brush border
cell cortex
postsynaptic density
NMDA selective glutamate receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281172
Coding exons: 20
Length: 262172
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.811	402	450	0.892	0.0000239	5417
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.299

Intolerance Scores

RVIS EVS: -0.3
RVIS percentile EVS: 32.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.871

Gene Damage Prediction

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