PGK1

protein-coding

phosphoglycerate kinase 1

Gene summary

The protein encoded by this gene is a glycolytic enzyme that catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. The encoded protein may also act as a cofactor for polymerase alpha. Additionally, this protein is secreted by tumor cells where it participates in angiogenesis by functioning to reduce disulfide bonds in the serine protease, plasmin, which consequently leads to the release of the tumor blood vessel inhibitor angiostatin. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Deficiency of the enzyme is associated with a wide range of clinical phenotypes hemolytic anemia and neurological impairment. Pseudogenes of this gene have been defined on chromosomes 19, 21 and the X chromosome. [provided by RefSeq, Jan 2014]

MANE transcript

NM_000291.4

Inheritance

XL, XLR

ClinVar variants

P:19U:188B:88

Top phenotype

Phosphoglycerate kinase 1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chrX:77,910,739-78,129,295

External References & Databases

Ensembl (ENSG00000102144)

Transcript & Mutation Effects

hg38 • Region Span ~218.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease due to phosphoglycerate kinase 1 deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010392

Submitter: PanelApp Australia

glycogen storage disease due to phosphoglycerate kinase 1 deficiencyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010392

Submitter: G2P

glycogen storage disease due to phosphoglycerate kinase 1 deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010392

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease due to phosphoglycerate kinase 1 deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010392

Submitter: Genomics England PanelApp

glycogen storage disease due to phosphoglycerate kinase 1 deficiencySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010392

Submitter: Orphanet

glycogen storage disease due to phosphoglycerate kinase 1 deficiencyDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010392

Submitter: Natera

Clinical Genomic Database (CGD)

Phosphoglycerate kinase 1 deficiencyXL

Manifestation: Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Hematologic; Musculoskeletal; Renal

Rationale: Individuals (males by report) may have partially transfusion-dependent anemia, as well as hemolytic crises requiring measures such as exchange transfusion; Rhabdomyolysis leading to acute renal failure has also been reported, and

Refs: 5764452; 6933565; 7082849; 3605066; 2715616; 1547346; 7577653; 9512313; 16412025; 16567715; 17222195; 22705348

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PGK1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 255

Glycogen storage disease due to phosphoglycerate kinase 1 deficiencyTotal: 113

not specifiedTotal: 44

Inborn genetic diseasesTotal: 31

PGK1-related disorderTotal: 22

Intellectual disabilityTotal: 2

Hereditary skeletal muscle disorderTotal: 1

Phosphoglycerate kinase electrophoretic variant PGK IITotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000291.4. 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	1 clinvar		6 clinvar	46 clinvar	4 clinvar	57
missense	11 clinvar	7 clinvar	172 clinvar	33 clinvar	4 clinvar	227
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			9 clinvar	1 clinvar		10
Total	12	7	188	80	8	295

Highest pathogenic variant AF is 9.221868e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000291.4	RefSeq	NP_000282.1	11	MANE Select
ENST00000373316.5	Ensembl	ENSP00000362413.4	11	MANE Select
ENST00000644362.1	Ensembl	ENSP00000496140.1	10	Standard
ENST00000878877.1	Ensembl	ENSP00000548936.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pgk1	Danio rerio	Structure: primary motor neuron Quality: swollen abnormal

Gene / Model

Organism

Observed Phenotype

pgk1

Danio rerio

Structure: primary motor neuron

Quality: swollen

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycolysis / Gluconeogenesis - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)
Lamivudine Pathway, Pharmacokinetics/Pharmacodynamics
Abacavir Pathway, Pharmacokinetics/Pharmacodynamics
Warburg Effect

Biological Process

gluconeogenesis
glycolytic process
phosphorylation
negative regulation of angiogenesis
epithelial cell differentiation

Molecular Function

phosphoglycerate kinase activity
protein binding
ATP binding
ADP binding
protein-disulfide reductase activity

Cellular Component

extracellular space
cytosol
membrane
membrane raft
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373316
Coding exons: 11
Length: 64109
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125718
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.338	144	156	0.924	0.0000110	2752
Missense (PolyPhen)		33	50.393	0.65485		1011
Synonymous	0.0294	57	57.3	0.995	0.00000395	826
Loss of Function	2.91	2	13.5	0.148	0.00000100	241

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000025	0.000018	rare
South Asian	0.000052	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: In addition to its role as a glycolytic enzyme, it seems that PGK-1 acts as a polymerase alpha cofactor protein (primer recognition protein) (PubMed:2324090). May play a role in sperm motility (PubMed:26677959). {ECO:0000269|PubMed:2324090, ECO:0000269|PubMed:26677959}.;

Recessive Scores

pRec: 0.973

Intolerance Scores

RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.932

Gene Damage Prediction

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