PMEL
protein-codingpremelanosome protein
Gene summary
This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]
- SIL
- SILV
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~19.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0018910
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PMEL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001384361.1. 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 | 6 | 1 | 7 | |||
| missense | 65 | 6 | 7 | 78 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 67 | 12 | 8 | 87 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001371290.1 | 11 | MANE Select | |
| Ensembl | ENSP00000448828.1 | 11 | MANE Select | |
| RefSeq | NP_001186982.1 | 9 | Standard | |
| RefSeq | NP_001186983.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pmelb | Danio rerio | Structure: retinal pigmented epithelium Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- melanosome organization
- melanin biosynthetic process
Molecular Function
- protein binding
- identical protein binding
Cellular Component
- extracellular region
- endoplasmic reticulum membrane
- Golgi apparatus
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000449260
- Coding exons
- 11
- Length
- 19213
- Individuals with no LoFs
- 125594
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 154
- Defined
- 125748
- p
- 0.000613
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.894 | 322 | 370 | 0.869 | 0.0000186 | 4260 |
| Missense (PolyPhen) | 123 | 140.9 | 0.87297 | 1724 | ||
| Synonymous | -0.132 | 148 | 146 | 1.01 | 0.00000747 | 1473 |
| Loss of Function | 0.310 | 28 | 29.8 | 0.939 | 0.00000153 | 307 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00092 | 0.00092 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00089 | 0.00089 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00092 | 0.00091 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a central role in the biogenesis of melanosomes. Involved in the maturation of melanosomes from stage I to II. The transition from stage I melanosomes to stage II melanosomes involves an elongation of the vesicle, and the appearance within of distinct fibrillar structures. Release of the soluble form, ME20-S, could protect tumor cells from antibody mediated immunity. {ECO:0000269|PubMed:11694580, ECO:0000269|PubMed:21962903}.;
Recessive Scores
- pRec
- 0.319
Intolerance Scores
- RVIS EVS
- -0.04
- RVIS percentile EVS
- 50.51
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |