EPOR

protein-coding

erythropoietin receptor, the group of Fibronectin type III domain containing

Gene summary

This gene encodes the erythropoietin receptor which is a member of the cytokine receptor family. Upon erythropoietin binding, this receptor activates Jak2 tyrosine kinase which activates different intracellular pathways including: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. The stimulated erythropoietin receptor appears to have a role in erythroid cell survival. Defects in the erythropoietin receptor may produce erythroleukemia and familial erythrocytosis. Dysregulation of this gene may affect the growth of certain tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

MANE transcript

NM_000121.4

Inheritance

ClinVar variants

P:7U:102B:47

Top phenotype

Erythrocytosis, familial, 1

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr19:11,377,207-11,384,342

External References & Databases

Ensembl (ENSG00000187266)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary familial polycythemia due to EPO receptor mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007572

Submitter: Orphanet

primary familial polycythemia due to EPO receptor mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007572

Submitter: Genomics England PanelApp

primary familial polycythemia due to EPO receptor mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007572

Submitter: Labcorp Genetics (formerly Invitae)

primary familial polycythemia due to EPO receptor mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007572

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Erythrocytosis, familial, 1AD

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Phlebotomy can be used to maintain the hematocrit value in the desired range

Refs: 4052634; 1954391; 093406; 9292543; 9649565; 20700488; 21437635

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPOR variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 65

not providedTotal: 59

Primary familial polycythemia due to EPO receptor mutationTotal: 56

not specifiedTotal: 28

EPOR-related disorderTotal: 8

Intellectual disability-hypotonic facies syndrome, X-linked, 1Total: 1

Acute megakaryoblastic leukemia without down syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000121.4. 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			7 clinvar	24 clinvar	1 clinvar	32
missense			85 clinvar	18 clinvar	4 clinvar	107
nonsense	2 clinvar	4 clinvar	2 clinvar			8
start loss						0
frameshift		1 clinvar	6 clinvar			7
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	5	102	42	5	156

Highest pathogenic variant AF is 0.0000780883

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000121.4	RefSeq	NP_000112.1	8	MANE Select
ENST00000222139.11	Ensembl	ENSP00000222139.5	8	MANE Select
ENST00000586890.5	Ensembl	ENSP00000467230.1	4	Standard
ENST00000588859.5	Ensembl	ENSP00000466784.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
epor	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

epor

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Hematopoietic cell lineage - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)

Biological Process

signal transduction
brain development
heart development
positive regulation of phosphatidylinositol 3-kinase signaling
erythropoietin-mediated signaling pathway

Molecular Function

erythropoietin receptor activity
protein binding
identical protein binding

Cellular Component

extracellular region
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222139
Coding exons: 8
Length: 6783
Individuals with no LoFs: 125710
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125746
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.14	238	293	0.813	0.0000143	3209
Missense (PolyPhen)		55	87.472	0.62877		1050
Synonymous	-0.262	136	132	1.03	0.00000663	1097
Loss of Function	2.72	7	20.2	0.347	8.72e-7	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000077	0.000062	rare
Latino/Admixed American	0.00042	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.000098	0.000098	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for erythropoietin. Mediates erythropoietin- induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase.;
Disease: DISEASE: Erythrocytosis, familial, 1 (ECYT1) [MIM:133100]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin and hematocrit, hypersensitivity of erythroid progenitors to erythropoietin, erythropoietin low serum levels, and no increase in platelets nor leukocytes. It has a relatively benign course and does not progress to leukemia. {ECO:0000269|PubMed:8506290, ECO:0000269|PubMed:8608241}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.238
RVIS EVS: 0.78
RVIS percentile EVS: 87.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.949

Gene Damage Prediction

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