GeneBe

GPNMB

protein-coding

glycoprotein nmb

Gene summary

The protein encoded by this gene is a type I transmembrane glycoprotein which shows homology to the pMEL17 precursor, a melanocyte-specific protein. GPNMB shows expression in the lowly metastatic human melanoma cell lines and xenografts but does not show expression in the highly metastatic cell lines. GPNMB may be involved in growth delay and reduction of metastatic potential. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002510.3

Inheritance

AR

ClinVar variants

P:16U:80B:30

Top phenotype

Amyloidosis, primary, localized cutaneous, 3

gnomAD constraint

pLI —, LoF o/e 1.27

Max pathogenic AF

—

Genomic locus

chr7:23,235,967-23,275,108

External References & Databases

Ensembl (ENSG00000136235)NCBI Gene (10457)OMIM (604368)HGNC:4462GenCCUniProt (Q14956)AlphaFoldClinVar (GPNMB)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~39.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyloidosis, primary localized cutaneous, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054765

Submitter: Labcorp Genetics (formerly Invitae)

amyloidosis, primary localized cutaneous, 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054765

Submitter: Ambry Genetics

amyloidosis, primary localized cutaneous, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054765

Submitter: PanelApp Australia

amyloidosis, primary localized cutaneous, 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054765

Submitter: G2P

Clinical Genomic Database (CGD)

Amyloidosis, primary, localized cutaneous, 3AR

Manifestation: Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19416385; 29336782Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPNMB variants in ClinVar

5 Conditions Cataloged
Inborn genetic diseasesTotal: 79
not providedTotal: 20
Amyloidosis, primary localized cutaneous, 3Total: 16
GPNMB-related disorderTotal: 13
not specifiedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002510.3. 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
10
clinvar
3
clinvar
 13
missense
1
clinvar
73
clinvar
12
clinvar
4
clinvar
 90
nonsense
3
clinvar
2
clinvar
1
clinvar
 6
start loss
0
frameshift
5
clinvar
2
clinvar
 7
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
7
clinvar
 10
Total9780237126

Highest pathogenic variant AF is 0.000725067

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002510.3RefSeqNP_002501.111MANE Select
ENST00000258733.9EnsemblENSP00000258733.511MANE Select
NM_001005340.2RefSeqNP_001005340.111Standard
ENST00000381990.6EnsemblENSP00000371420.211Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling by PTK6
  • Signal Transduction
  • PTK6 promotes HIF1A stabilization
  • Signaling by Non-Receptor Tyrosine Kinases

Biological Process

  • osteoblast differentiation
  • negative regulation of cytokine production
  • positive regulation of protein phosphorylation
  • cell adhesion
  • signal transduction

Molecular Function

  • integrin binding
  • protein binding
  • heparin binding
  • chemoattractant activity
  • syndecan binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • integral component of membrane
  • early endosome membrane
  • melanosome membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000381990
Coding exons
11
Length
39142
Individuals with no LoFs
125403
Homozygous LoFs
1
Heterozygous LoFs
344
Defined
125748
p
0.00137
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1243183240.9810.00001733752
Missense (PolyPhen)8691.990.934891142
Synonymous0.1161301320.9870.000008041124
Loss of Function-1.353628.21.270.00000161302

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000550.00055rare
Latino/Admixed American0.00170.0017notable
Ashkenazi Jewish0.00180.0018notable
East Asian0.00400.0040notable
Finnish0.0000920.000092rare
European (Non-Finnish)0.00130.0013notable
South Asian0.000920.00088rare
Other0.000820.00081rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Could be a melanogenic enzyme. {ECO:0000250}.;
Disease
DISEASE: Note=Increased expression levels in glioblastoma multiforme biopsy samples correlate with poor patient survival prognosis (PubMed:16609006). Has been proposed as a potential target for antibodies coupled to cytotoxic drugs in the context of cancer immunotherapy, including that of melanoma (PubMed:16489096). {ECO:0000269|PubMed:16489096, ECO:0000269|PubMed:16609006}.; DISEASE: Amyloidosis, primary localized cutaneous, 3 (PLCA3) [MIM:617920]: A primary amyloidosis characterized by localized cutaneous amyloid deposition. This condition usually presents with itching (especially on the lower legs) and visible changes of skin hyperpigmentation and thickening that may be exacerbated by chronic scratching and rubbing. Primary localized cutaneous amyloidosis is often divided into macular and lichen subtypes although many affected individuals often show both variants coexisting. Lichen amyloidosis characteristically presents as a pruritic eruption of grouped hyperkeratotic papules with a predilection for the shins, calves, ankles and dorsa of feet and thighs. Papules may coalesce to form hyperkeratotic plaques that can resemble lichen planus, lichen simplex or nodular prurigo. Macular amyloidosis is characterized by small pigmented macules that may merge to produce macular hyperpigmentation, sometimes with a reticulate or rippled pattern. In macular and lichen amyloidosis, amyloid is deposited in the papillary dermis in association with grouped colloid bodies, thought to represent degenerate basal keratinocytes. The amyloid deposits probably reflect a combination of degenerate keratin filaments, serum amyloid P component, and deposition of immunoglobulins. PLCA3 inheritance is autosomal recessive. {ECO:0000269|PubMed:29336782}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.135

Intolerance Scores

LoFtool
0.984
RVIS EVS
0.89
RVIS percentile EVS
89.29

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.186

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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