GMPPB

GDP-mannose pyrophosphorylase B

Basic information

Region (hg38): 3:49716843-49723973

Links

ENSG00000173540 ∙ NCBI:29925 ∙ OMIM:615320 ∙ HGNC:22932 ∙ Uniprot:Q9Y5P6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (Definitive), mode of inheritance: AR
• congenital myasthenic syndrome (Strong), mode of inheritance: AR
• autosomal recessive limb-girdle muscular dystrophy type 2T (Strong), mode of inheritance: AR
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (Strong), mode of inheritance: AR
• autosomal recessive limb-girdle muscular dystrophy type 2T (Moderate), mode of inheritance: AR
• muscle-eye-brain disease (Supportive), mode of inheritance: AR
• congenital myasthenic syndromes with glycosylation defect (Supportive), mode of inheritance: AR
• autosomal recessive limb-girdle muscular dystrophy type 2T (Supportive), mode of inheritance: AR
• congenital muscular dystrophy with cerebellar involvement (Supportive), mode of inheritance: AR
• congenital muscular dystrophy with intellectual disability (Supportive), mode of inheritance: AR
• autosomal recessive limb-girdle muscular dystrophy type 2T (Strong), mode of inheritance: AR
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (Strong), mode of inheritance: AR
• myopathy caused by variation in GMPPB (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14; Limb-girdle muscular dystrophy-dystroglycanopathy, type B, 14; Limb-girdle muscular dystrophy-dystroglycanopathy, type C, 14	AR	Cardiovascular	Cardiovascular complications, including long QT syndrome and cardiomyopathy, have been described, and awareness may allow surveillance and prompt management	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic	23768512

ClinVar

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

• Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;Autosomal recessive limb-girdle muscular dystrophy type 2T (124 variants)
• not provided (98 variants)
• Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;Autosomal recessive limb-girdle muscular dystrophy type 2T;Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (80 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2T;Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (33 variants)
• Inborn genetic diseases (26 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2T (18 variants)
• not specified (15 variants)
• Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;Autosomal recessive limb-girdle muscular dystrophy type 2T (15 variants)
• Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (12 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2T;Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (8 variants)
• Abnormality of the musculature (6 variants)
• Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (5 variants)
• GMPPB-Related Disorders (4 variants)
• Muscular dystrophy (2 variants)
• GMPPB-related condition (2 variants)
• Muscular dystrophy-dystroglycanopathy (2 variants)
• Global developmental delay (1 variants)
• Myopathy caused by variation in GMPPB (1 variants)
• - (1 variants)
• Elevated circulating creatine kinase concentration (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GMPPB 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			2	61	1	64
missense	4	13	126		2	145
nonsense	6		1			7
start loss						0
frameshift	7	6				13
inframe indel			6			6
splice donor/acceptor (+/-2bp)	2	5	1			8
splice region			10	12		22
non coding		1	18	41	3	63
Total	19	25	154	102	6

Highest pathogenic variant AF is 0.0000657

Variants in GMPPB

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

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

Position	Type	Phenotype	Significance	ClinVar
3-49717989-C-A		not specified	Uncertain significance (Nov 22, 2022)
3-49718001-C-T		not specified	Uncertain significance (Apr 25, 2022)
3-49718006-T-C		not specified	Uncertain significance (Mar 21, 2022)
3-49718103-C-G		not specified	Uncertain significance (Oct 10, 2023)
3-49718106-C-G		not specified	Uncertain significance (Aug 02, 2022)
3-49718110-C-G		not specified	Uncertain significance (Jan 26, 2022)
3-49718209-C-CCAGCGGCGG			Benign (Jul 01, 2022)
3-49718213-C-T		not specified	Uncertain significance (Jan 20, 2023)
3-49718232-G-C		not specified	Uncertain significance (Jul 15, 2021)
3-49718244-G-C		not specified	Uncertain significance (Jun 29, 2023)
3-49718307-T-C		not specified	Uncertain significance (May 31, 2023)
3-49718425-C-T			Likely benign (Aug 01, 2022)
3-49718427-C-T		not specified	Uncertain significance (Nov 08, 2022)
3-49718510-A-C		not specified	Uncertain significance (Jun 14, 2023)
3-49718514-G-C		not specified	Uncertain significance (May 01, 2022)
3-49718515-C-A		not specified	Uncertain significance (Feb 26, 2024)
3-49718544-G-T		not specified	Uncertain significance (Jan 18, 2022)
3-49718622-C-G		not specified	Uncertain significance (Dec 05, 2022)
3-49718653-C-G		not specified	Uncertain significance (Oct 27, 2022)
3-49718670-G-A		not specified	Uncertain significance (May 23, 2023)
3-49718696-G-A		not specified	Uncertain significance (May 15, 2023)
3-49718748-T-C		not specified	Uncertain significance (Oct 27, 2022)
3-49718943-C-G		not specified	Uncertain significance (Apr 07, 2023)
3-49719015-G-A		not specified	Uncertain significance (Sep 06, 2022)
3-49719037-G-T		not specified	Uncertain significance (Sep 01, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GMPPB	protein_coding	protein_coding	ENST00000308375	8	7108

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.44e-7	0.759	125714	0	30	125744	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.02	205	250	0.819	0.0000152	2498
Missense in Polyphen		68	98.036	0.69362		1008
Synonymous	-0.454	108	102	1.06	0.00000605	800
Loss of Function	1.28	12	17.8	0.674	8.10e-7	193

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000478	0.000478
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000793	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.000294	0.000294
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids. {ECO:0000250|UniProtKB:P0C5I2}.
• Disease: DISEASE: Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A14 (MDDGA14) [MIM:615350]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with brain anomalies, eye malformations, and profound mental retardation. The disorder includes a severe form designated as Walker-Warburg syndrome and a less severe phenotype known as muscle-eye-brain disease. MDDGA14 features include increased muscle tone, microcephaly, cleft palate, feeding difficulties, severe muscle weakness, sensorineural hearing loss, cerebellar hypoplasia, ataxia, and retinal dysfunction. {ECO:0000269|PubMed:23768512}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy congenital with mental retardation B14 (MDDGB14) [MIM:615351]: A congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and mental retardation. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. {ECO:0000269|PubMed:23768512}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C14 (MDDGC14) [MIM:615352]: An autosomal recessive form of muscular dystrophy characterized by mild proximal muscle weakness with onset in early childhood. Some patients may have additional features, such as mild intellectual disability or seizures. {ECO:0000269|PubMed:23768512, ECO:0000269|PubMed:26310427, ECO:0000269|PubMed:28433477, ECO:0000269|PubMed:28478914}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Fructose and mannose metabolism - Homo sapiens (human);Amino sugar and nucleotide sugar metabolism - Homo sapiens (human);Fructose intolerance, hereditary;Fructose and Mannose Degradation;Fructosuria;Fructose Mannose metabolism;Post-translational protein modification;Metabolism of proteins;Synthesis of GDP-mannose;Synthesis of substrates in N-glycan biosythesis;Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein;Asparagine N-linked glycosylation;GDP-mannose biosynthesis (Consensus)

Recessive Scores

• pRec: 0.196

Intolerance Scores

• rvis_EVS: -0.34
• rvis_percentile_EVS: 30.56

Haploinsufficiency Scores

• pHI: 0.825
• hipred: Y
• hipred_score: 0.550
• ghis: 0.423

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.976

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gmppb

Zebrafish Information Network

• Gene name: gmppb
• Affected structure: skeletal muscle cell
• Phenotype tag: abnormal
• Phenotype quality: sparse

Gene ontology

• Biological process: GDP-mannose biosynthetic process
• Cellular component: cytoplasm
• Molecular function: mannose-1-phosphate guanylyltransferase activity;protein binding;GTP binding