GMPPA

GDP-mannose pyrophosphorylase A

Basic information

Region (hg38): 2:219498865-219513898

Links

ENSG00000144591 ∙ NCBI:29926 ∙ OMIM:615495 ∙ HGNC:22923 ∙ Uniprot:Q96IJ6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• alacrima, achalasia, and intellectual disability syndrome (Strong), mode of inheritance: AR
• triple-A syndrome (Supportive), mode of inheritance: AR
• alacrima, achalasia, and intellectual disability syndrome (Definitive), mode of inheritance: AR
• alacrima, achalasia, and intellectual disability syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alacrima, achalasia, and impaired intellectual development syndrome	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	Audiologic/Otolaryngologic; Dermatologic; Gastrointestinal; Neurologic; Ophthalmologic	24035193
Onset and severity of hearing impairment is unclear

ClinVar

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

• Alacrima, achalasia, and intellectual disability syndrome (3 variants)
• Global developmental delay;Gastroesophageal reflux (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GMPPA 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			1	31	3	35
missense			43	2		45
nonsense		4	1			5
start loss						0
frameshift	2	1				3
inframe indel						0
splice donor/acceptor (+/-2bp)	1	1				2
splice region			3	2		5
non coding				22	10	32
Total	3	6	45	55	13

Variants in GMPPA

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

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

Position	Type	Phenotype	Significance	ClinVar
2-219499236-T-C			Benign (Mar 17, 2021)
2-219499241-T-C		not specified	Likely benign (Jan 04, 2018)
2-219499740-TATTTGGG-T			Benign (May 12, 2021)
2-219499987-G-A		Alacrima, achalasia, and intellectual disability syndrome	Uncertain significance (Sep 01, 2021)
2-219500028-G-A		not specified • Alacrima, achalasia, and intellectual disability syndrome	Likely benign (Nov 27, 2023)
2-219500030-G-A		not specified • Alacrima, achalasia, and intellectual disability syndrome	Benign/Likely benign (Jan 05, 2024)
2-219500035-G-A		Alacrima, achalasia, and intellectual disability syndrome	Likely benign (May 09, 2023)
2-219500105-C-T		Alacrima, achalasia, and intellectual disability syndrome	Likely benign (Sep 21, 2023)
2-219500126-C-T		Inborn genetic diseases	Uncertain significance (Jun 03, 2024)
2-219500146-T-C		Alacrima, achalasia, and intellectual disability syndrome	Likely benign (Dec 31, 2019)
2-219500188-G-C		Alacrima, achalasia, and intellectual disability syndrome • Inborn genetic diseases	Uncertain significance (Feb 23, 2023)
2-219500196-AC-A		Alacrima, achalasia, and intellectual disability syndrome	Pathogenic (Oct 17, 2023)
2-219500197-C-T		Alacrima, achalasia, and intellectual disability syndrome	Likely benign (Oct 28, 2023)
2-219500213-G-A		Inborn genetic diseases	Uncertain significance (Feb 15, 2023)
2-219500219-G-T			Likely pathogenic (Mar 18, 2022)
2-219500226-C-T		not specified	Likely benign (Jan 11, 2017)
2-219500226-CAG-C		Alacrima, achalasia, and intellectual disability syndrome	Likely benign (Jul 19, 2018)
2-219501513-A-G		Inborn genetic diseases	Uncertain significance (May 24, 2024)
2-219501527-C-T		not specified • Alacrima, achalasia, and intellectual disability syndrome • GMPPA-related disorder	Benign/Likely benign (Jan 13, 2024)
2-219501530-C-T		Alacrima, achalasia, and intellectual disability syndrome	Uncertain significance (Jun 15, 2022)
2-219501538-G-T		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
2-219501545-GA-G		Alacrima, achalasia, and intellectual disability syndrome • Global developmental delay;Gastroesophageal reflux	Pathogenic (Jan 24, 2023)
2-219501550-C-T		not specified • Alacrima, achalasia, and intellectual disability syndrome	Benign/Likely benign (Jan 31, 2024)
2-219501551-G-A		Alacrima, achalasia, and intellectual disability syndrome	Conflicting classifications of pathogenicity (Nov 27, 2023)
2-219501561-A-C		Inborn genetic diseases	Uncertain significance (Apr 15, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GMPPA	protein_coding	protein_coding	ENST00000358215	12	8122

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.36e-9	0.905	125704	0	44	125748	0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.21	205	260	0.789	0.0000160	2687
Missense in Polyphen		65	96.682	0.6723		1046
Synonymous	0.501	96	102	0.937	0.00000633	844
Loss of Function	1.79	17	27.0	0.629	0.00000161	254

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000268	0.000268
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.000601	0.000601
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.000163	0.000163
South Asian	0.000197	0.000196
Other	0.000514	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May serve as a regulatory subunit and allow allosteric feedback inhibition of GMPPB by GDP-mannose. {ECO:0000269|PubMed:24035193}.
• Pathway: Fructose and mannose metabolism - Homo sapiens (human);Amino sugar and nucleotide sugar metabolism - Homo sapiens (human);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: 0.115

Intolerance Scores

• loftool: 0.343
• rvis_EVS: -0.29
• rvis_percentile_EVS: 33.34

Haploinsufficiency Scores

• pHI: 0.368
• hipred: N
• hipred_score: 0.407
• ghis: 0.546

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.993

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gmppa

Gene ontology

• Biological process: biosynthetic process
• Cellular component: cytoplasm;extracellular exosome
• Molecular function: protein binding;nucleotidyltransferase activity