EPO

protein-coding

erythropoietin, the group of Receptor ligands

Gene summary

This gene encodes a secreted, glycosylated cytokine composed of four alpha helical bundles. The encoded protein is mainly synthesized in the kidney, secreted into the blood plasma, and binds to the erythropoietin receptor to promote red blood cell production, or erythropoiesis, in the bone marrow. Expression of this gene is upregulated under hypoxic conditions, in turn leading to increased erythropoiesis and enhanced oxygen-carrying capacity of the blood. Expression of this gene has also been observed in brain and in the eye, and elevated expression levels have been observed in diabetic retinopathy and ocular hypertension. Recombinant forms of the encoded protein exhibit neuroprotective activity against a variety of potential brain injuries, as well as antiapoptotic functions in several tissue types, and have been used in the treatment of anemia and to enhance the efficacy of cancer therapies. [provided by RefSeq, Aug 2017]

MANE transcript

NM_000799.4

Inheritance

AD, AR

ClinVar variants

P:3U:29B:19

Top phenotype

Erythrocytosis, familial, 5; Diamond-Blackfan anemia-like

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr7:100,720,468-100,723,700

External References & Databases

Ensembl (ENSG00000130427)

Transcript & Mutation Effects

hg38 • Region Span ~3.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Diamond-Blackfan anemia-likeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0060662

Submitter: Labcorp Genetics (formerly Invitae)

erythrocytosis, familial, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033483

Submitter: PanelApp Australia

erythrocytosis, familial, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033483

Submitter: Genomics England PanelApp

erythrocytosis, familial, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033483

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant secondary polycythemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016599

Submitter: Orphanet

Diamond-Blackfan anemia-likeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060662

Submitter: Ambry Genetics

erythrocytosis, familial, 5LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033483

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Erythrocytosis, familial, 5; Diamond-Blackfan anemia-likeAD/AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: For Erythrocytosis, phlebotomy can be used to maintain the hematocrit value in the desired range; Individuals with Diamond-Blackfan anemia-like may benefit from medical management (recombinant EPO has been described), and HSCT has been reported

Refs: 27651169; 28283061; 29514032

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPO variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 36

not providedTotal: 20

EPO-related disorderTotal: 16

Erythrocytosis, familial, 5Total: 2

Diamond-Blackfan anemia-likeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000799.4. 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				13 clinvar	1 clinvar	14
missense	1 clinvar		27 clinvar	5 clinvar		33
nonsense						0
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	0	29	18	1	51

Highest pathogenic variant AF is 0.0000037176565

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000799.4	RefSeq	NP_000790.2	5	MANE Select
ENST00000252723.3	Ensembl	ENSP00000252723.2	5	MANE Select
ENST00001142688.1	Ensembl	ENSP00000802629.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

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

Gene / Model

Organism

Observed Phenotype

epoa

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)
HIF-1 signaling pathway - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Hematopoietic cell lineage - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
response to hypoxia
apoptotic process
acute-phase response
signal transduction

Molecular Function

cytokine activity
erythropoietin receptor binding
hormone activity
protein binding
protein kinase activator activity

Cellular Component

extracellular region
extracellular space
cell surface
cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252723
Coding exons: 5
Length: 2901
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125746
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.559	97	114	0.853	0.00000685	1201
Missense (PolyPhen)		28	38.334	0.73042		439
Synonymous	-0.830	57	49.6	1.15	0.00000275	432
Loss of Function	1.82	5	11.7	0.426	7.59e-7	104

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation and the maintenance of a physiological level of circulating erythrocyte mass. Binds to EPOR leading to EPOR dimerization and JAK2 activation thereby activating specific downstream effectors, including STAT1 and STAT3. {ECO:0000269|PubMed:28283061}.;
Disease: DISEASE: Erythrocytosis, familial, 5 (ECYT5) [MIM:617907]: An autosomal dominant disorder characterized by increased serum red blood cell mass, and elevated serum hemoglobin and hematocrit. Some patients have increased serum erythropoietin levels. {ECO:0000269|PubMed:27651169, ECO:0000269|PubMed:29514032}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diamond-Blackfan anemia-like (DBAL) [MIM:617911]: An autosomal recessive hematologic disease characterized by severe red cell hypoplastic anemia, selective absence of red cell precursors and progenitors seen on bone marrow biopsy, and increased serum erythropoietin. {ECO:0000269|PubMed:28283061}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.802

Intolerance Scores

LoFtool: 0.354
RVIS EVS: 0.64
RVIS percentile EVS: 83.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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