POMC
protein-codingproopiomelanocortin, the group of Neuropeptides
Gene summary
This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019182
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012335
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012335
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012335
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012335
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012335
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0019182
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Endocrine
Intervention: Endocrine
Rationale: The condition can present with adrenal insufficiency, and medical treatment (eg, with glucocorticoid replacement therapy) can be beneficial, though may not affect certain manifestations such as obesity; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POMC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000939.4. 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 | 4 | 57 | 61 | |||
| missense | 3 | 134 | 7 | 1 | 145 | |
| nonsense | 5 | 3 | 7 | 15 | ||
| start loss | 0 | |||||
| frameshift | 5 | 8 | 5 | 18 | ||
| splice donor/acceptor (+/-2bp) | 3 | 1 | 4 | |||
| Total | 13 | 15 | 150 | 64 | 1 | 243 |
Highest pathogenic variant AF is 0.00007267189
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000930.1 | 2 | MANE Select | |
| Ensembl | ENSP00000379170.2 | 2 | MANE Select | |
| RefSeq | NP_001030333.1 | 2 | Standard | |
| RefSeq | NP_001306133.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pomca | Danio rerio | Structure: melanocyte Quality: aggregated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cortisol synthesis and secretion - Homo sapiens (human)
- Aldosterone synthesis and secretion - Homo sapiens (human)
- Adipocytokine signaling pathway - Homo sapiens (human)
- Cushing,s syndrome - Homo sapiens (human)
- Melanogenesis - Homo sapiens (human)
Biological Process
- generation of precursor metabolites and energy
- signal transduction
- G protein-coupled receptor signaling pathway
- neuropeptide signaling pathway
- cell-cell signaling
Molecular Function
- G protein-coupled receptor binding
- signaling receptor binding
- hormone activity
- type 3 melanocortin receptor binding
- type 4 melanocortin receptor binding
Cellular Component
- extracellular region
- extracellular space
- cytoplasm
- secretory granule
- secretory granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000405623
- Coding exons
- 2
- Length
- 8051
- Individuals with no LoFs
- 125607
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 138
- Defined
- 125745
- p
- 0.000549
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.103 | 188 | 192 | 0.979 | 0.0000136 | 1701 |
| Missense (PolyPhen) | 59 | 62.589 | 0.94266 | 611 | ||
| Synonymous | 0.785 | 83 | 92.6 | 0.896 | 0.00000747 | 529 |
| Loss of Function | 0.740 | 7 | 9.46 | 0.740 | 4.97e-7 | 94 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.0017 | 0.0016 | notable |
| European (Non-Finnish) | 0.00073 | 0.00071 | rare |
| South Asian | 0.00034 | 0.00033 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Corticotropin: Stimulates the adrenal glands to release cortisol.; FUNCTION: Melanocyte-stimulating hormone beta: Increases the pigmentation of skin by increasing melanin production in melanocytes.; FUNCTION: Met-enkephalin: Endogenous opiate.;
- Disease
- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:12165561}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Obesity, early-onset, with adrenal insufficiency and red hair (OBAIRH) [MIM:609734]: An autosomal recessive disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair, and secondary hypocortisolism. {ECO:0000269|PubMed:9620771}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.981
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.708
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |