EXPH5

protein-coding

exophilin 5

Gene summary

The protein encoded by this gene is a member of the synaptotagmin-like protein (Slp) family lacking a C2 domain. It contains an N-terminal synaptotagmin-like homology domain (SHD), and is a ras-related protein Rab-27B effector protein. This protein is thought to be involved in exosome secretion and intracellular vesicle trafficking. Reduced expression of this gene results in keratin filament defects. Mutations in this gene have been associated with some cases of epidermolysis bullosa, an inherited skin fragility disorder. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

MANE transcript

NM_015065.3

Inheritance

ClinVar variants

P:20U:290B:118

Top phenotype

Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr11:108,505,435-108,593,768

External References & Databases

Ensembl (ENSG00000110723)

Transcript & Mutation Effects

hg38 • Region Span ~88.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014014

Submitter: Orphanet

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014014

Submitter: G2P

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014014

Submitter: PanelApp Australia

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014014

Submitter: Labcorp Genetics (formerly Invitae)

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014014

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveAR

Manifestation: Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Though appropriate skin care may be beneficial, it is unclear if early (genetic) diagnosis would be additionally advantageous

Refs: 23176819

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EXPH5 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 288

not providedTotal: 133

EXPH5-related disorderTotal: 62

Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessiveTotal: 23

not specifiedTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015065.3. 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			1 clinvar	44 clinvar	11 clinvar	56
missense			280 clinvar	42 clinvar	21 clinvar	343
nonsense	3 clinvar	5 clinvar	5 clinvar			13
start loss						0
frameshift	8 clinvar	4 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	11	9	290	86	32	428

Highest pathogenic variant AF is 0.0000639049

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015065.3	RefSeq	NP_055880.2	6	MANE Select
ENST00000265843.9	Ensembl	ENSP00000265843.4	6	MANE Select
NM_001144763.2	RefSeq	NP_001138235.1	5	Standard
NM_001144764.2	RefSeq	NP_001138236.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Deregulation of Rab and Rab Effector Genes in Bladder Cancer

Biological Process

keratinocyte development
intracellular protein transport
positive regulation of exocytosis
positive regulation of protein secretion
multivesicular body sorting pathway

Molecular Function

Rab GTPase binding

Cellular Component

endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265843
Coding exons: 6
Length: 88308
Individuals with no LoFs: 125524
Homozygous LoFs: 0
Heterozygous LoFs: 224
Defined: 125748
p: 0.000891

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.274	1025	1.00e+3	1.02	0.0000479	13092
Missense (PolyPhen)		195	222.63	0.87589		3194
Synonymous	0.605	361	376	0.960	0.0000194	3810
Loss of Function	1.93	49	65.9	0.743	0.00000349	906

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.0014	0.0012	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0014	0.0014	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.00067	0.00065	rare
Other	0.00084	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as Rab effector protein and play a role in vesicle trafficking.;

Recessive Scores

pRec: 0.0918

Intolerance Scores

LoFtool: 0.971
RVIS EVS: 4.12
RVIS percentile EVS: 99.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.661

Gene Damage Prediction

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