GeneBe

GPI

protein-coding

glucose-6-phosphate isomerase

Gene summary

This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme (glucose-6-phosphate isomerase) that interconverts glucose-6-phosphate and fructose-6-phosphate. Extracellularly, the encoded protein (also referred to as neuroleukin) functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

MANE transcript

NM_000175.5

Inheritance

AR, AD

ClinVar variants

P:36U:139B:56

Top phenotype

Anemia, congenital, nonspherocytic hemolytic, 4

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr19:34,359,480-34,402,413

External References & Databases

Ensembl (ENSG00000105220)NCBI Gene (2821)OMIM (172400)HGNC:4458GenCCUniProt (P06744)AlphaFoldClinVar (GPI)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~42.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemolytic anemia due to glucophosphate isomerase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013275

Submitter: Orphanet

hemolytic anemia due to glucophosphate isomerase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013275

Submitter: Labcorp Genetics (formerly Invitae)

hemolytic anemia due to glucophosphate isomerase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013275

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Anemia, congenital, nonspherocytic hemolytic, 4AD

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: Anemia may be ameliorated by splenectomy, and it may be beneficial to avoid agents (or provide monitoring if such agents are unavoidable) that may precipitate hemolytic anemia

Refs: 5672849; 469896; 3796702; 10916680; 17041899; 20516363; 22782259Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPI variants in ClinVar

9 Conditions Cataloged
Hemolytic anemia due to glucophosphate isomerase deficiencyTotal: 117
not providedTotal: 102
Inborn genetic diseasesTotal: 58
GPI-related disorderTotal: 19
not specifiedTotal: 18
GPI-related disordersTotal: 2
Hereditary spherocytosisTotal: 1
Intellectual disability, autosomal recessive 42Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000175.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
43
clinvar
3
clinvar
 48
missense
11
clinvar
9
clinvar
125
clinvar
9
clinvar
1
clinvar
 155
nonsense
1
clinvar
3
clinvar
 4
start loss
0
frameshift
2
clinvar
5
clinvar
1
clinvar
 8
splice donor/acceptor (+/-2bp)
5
clinvar
11
clinvar
 16
Total1422139524231

Highest pathogenic variant AF is 0.00007686128

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000175.5RefSeqNP_000166.218MANE Select
ENST00000356487.11EnsemblENSP00000348877.318MANE Select
NM_001184722.1RefSeqNP_001171651.118Standard
NM_001289789.1RefSeqNP_001276718.119Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • UDP-<i>N</i>-acetyl-D-galactosamine biosynthesis II
  • Glycolysis / Gluconeogenesis - Homo sapiens (human)
  • Starch and sucrose metabolism - Homo sapiens (human)
  • Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
  • Pentose phosphate pathway - Homo sapiens (human)

Biological Process

  • in utero embryonic development
  • mesoderm formation
  • carbohydrate metabolic process
  • gluconeogenesis
  • glycolytic process

Molecular Function

  • glucose-6-phosphate isomerase activity
  • cytokine activity
  • growth factor activity
  • intramolecular transferase activity
  • ubiquitin protein ligase binding

Cellular Component

  • extracellular region
  • nucleoplasm
  • cytosol
  • plasma membrane
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000415930
Coding exons
18
Length
42677
Individuals with no LoFs
125684
Homozygous LoFs
0
Heterozygous LoFs
64
Defined
125748
p
0.000255
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.132733310.8250.00002073731
Missense (PolyPhen)100143.120.698691686
Synonymous-0.06761341331.010.000009061104
Loss of Function2.971533.50.4470.00000163376

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000230.00020rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000200.00016rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000230.00023rare
South Asian0.000810.00072rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Besides it's role as a glycolytic enzyme, mammalian GPI can function as a tumor-secreted cytokine and an angiogenic factor (AMF) that stimulates endothelial cell motility. GPI is also a neurotrophic factor (Neuroleukin) for spinal and sensory neurons. {ECO:0000269|PubMed:11004567, ECO:0000269|PubMed:11437381}.;
Disease
DISEASE: Hemolytic anemia, non-spherocytic, due to glucose phosphate isomerase deficiency (HA-GPID) [MIM:613470]: A form of anemia in which there is no abnormal hemoglobin or spherocytosis. It is caused by glucose phosphate isomerase deficiency. {ECO:0000269|PubMed:7989588, ECO:0000269|PubMed:8499925, ECO:0000269|PubMed:8822952, ECO:0000269|PubMed:8822954, ECO:0000269|PubMed:9446754, ECO:0000269|PubMed:9856489}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.859

Intolerance Scores

LoFtool
0.0584
RVIS EVS
-0.91
RVIS percentile EVS
10.03

Essentials

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

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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