GPNMB

glycoprotein nmb

Basic information

Region (hg38): 7:23235967-23275108

Links

ENSG00000136235 ∙ NCBI:10457 ∙ OMIM:604368 ∙ HGNC:4462 ∙ Uniprot:Q14956 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyloidosis, primary localized cutaneous, 3 (Moderate), mode of inheritance: AR
• amyloidosis, primary localized cutaneous, 3 (Strong), mode of inheritance: AR
• amyloidosis, primary localized cutaneous, 3 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyloidosis, primary, localized cutaneous, 3	AR	General	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	Dermatologic	19416385; 29336782

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GPNMB gene.

• Amyloidosis, primary localized cutaneous, 3 (4 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GPNMB gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				6	3	9
missense			48	7	4	59
nonsense	2	1		1		4
start loss						0
frameshift	2	2				4
inframe indel						0
splice donor/acceptor (+/-2bp)	1	1				2
splice region						0
non coding						0
Total	5	4	48	14	7

Highest pathogenic variant AF is 0.000164

Variants in GPNMB

This is a list of pathogenic ClinVar variants found in the GPNMB region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-23246865-G-T		Inborn genetic diseases	Uncertain significance (Jul 02, 2024)
7-23246867-C-T		Inborn genetic diseases	Uncertain significance (Mar 01, 2024)
7-23246890-G-A		GPNMB-related disorder	Benign (Dec 24, 2018)
7-23246906-T-C		GPNMB-related disorder	Benign (Mar 27, 2019)
7-23246910-C-T			Likely benign (Dec 31, 2019)
7-23246921-G-T		Inborn genetic diseases	Uncertain significance (Oct 10, 2023)
7-23246922-C-A		Inborn genetic diseases	Uncertain significance (Apr 04, 2024)
7-23253412-A-C		Inborn genetic diseases	Uncertain significance (Jun 24, 2022)
7-23253427-G-A		Inborn genetic diseases	Uncertain significance (Jan 31, 2022)
7-23254171-G-T			Likely benign (Mar 01, 2024)
7-23254202-C-T		Inborn genetic diseases	Uncertain significance (Nov 05, 2021)
7-23254212-C-T			Likely benign (Dec 31, 2019)
7-23254235-C-T			Benign (Sep 19, 2018)
7-23254237-G-A		Inborn genetic diseases	Uncertain significance (Oct 22, 2024)
7-23254239-GA-G		Amyloidosis, primary localized cutaneous, 3	Pathogenic (Mar 27, 2018)
7-23254254-TAGATGCCAAAAGGA-T		Amyloidosis, primary localized cutaneous, 3 • GPNMB-related disorder	Pathogenic/Likely pathogenic (Aug 23, 2019)
7-23254279-G-A		Inborn genetic diseases	Uncertain significance (Sep 10, 2024)
7-23254284-C-T			Likely benign (Feb 25, 2018)
7-23256914-G-A		GPNMB-related disorder	Benign (Oct 23, 2019)
7-23256917-T-G		Amyloidosis, primary localized cutaneous, 3	Pathogenic (-)
7-23256945-G-T		GPNMB-related disorder	Likely benign (Dec 31, 2019)
7-23256953-C-T		GPNMB-related disorder	Benign (Feb 28, 2019)
7-23256954-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
7-23256993-C-T		Inborn genetic diseases	Uncertain significance (Jul 14, 2021)
7-23257050-G-A		Inborn genetic diseases	Uncertain significance (Jan 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GPNMB	protein_coding	protein_coding	ENST00000381990	11	39142

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.88e-27	0.00000806	125403	1	344	125748	0.00137

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.124	318	324	0.981	0.0000173	3752
Missense in Polyphen		86	91.99	0.93489		1142
Synonymous	0.116	130	132	0.987	0.00000804	1124
Loss of Function	-1.35	36	28.2	1.27	0.00000161	302

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00230	0.00230
Ashkenazi Jewish	0.00179	0.00179
East Asian	0.00402	0.00398
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.00133	0.00133
Middle Eastern	0.00402	0.00398
South Asian	0.000922	0.000882
Other	0.000816	0.000815

dbNSFP

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.
• Pathway: Signaling by PTK6;Signal Transduction;PTK6 promotes HIF1A stabilization;Signaling by Non-Receptor Tyrosine Kinases (Consensus)

Recessive Scores

• pRec: 0.135

Intolerance Scores

• loftool: 0.984
• rvis_EVS: 0.89
• rvis_percentile_EVS: 89.29

Haploinsufficiency Scores

• pHI: 0.702
• hipred: N
• hipred_score: 0.180
• ghis: 0.445

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.186

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gpnmb
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; neoplasm; pigmentation phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; homeostasis/metabolism phenotype; immune system phenotype

Gene ontology

• Biological process: osteoblast differentiation;negative regulation of cytokine production;positive regulation of protein phosphorylation;cell adhesion;signal transduction;cell-cell signaling;negative regulation of cell population proliferation;regulation of signaling receptor activity;bone mineralization;positive regulation of cell migration;positive regulation of protein autophosphorylation;negative regulation of tumor necrosis factor production;regulation of tissue remodeling;negative regulation of T cell proliferation;regulation of angiogenesis;negative regulation of T cell activation;positive chemotaxis;positive regulation of ERK1 and ERK2 cascade;negative regulation of neuron death;negative regulation of G1/S transition of mitotic cell cycle
• Cellular component: plasma membrane;integral component of plasma membrane;integral component of membrane;early endosome membrane;melanosome membrane
• Molecular function: integrin binding;protein binding;heparin binding;chemoattractant activity;syndecan binding;receptor ligand activity