GeneBe

AGA

protein-coding

aspartylglucosaminidase

Gene summary

This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]

MANE transcript

NM_000027.4

Inheritance

AR

ClinVar variants

P:129U:131B:147

Top phenotype

Aspartylglucosaminuria

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr4:177,430,774-177,442,437

External References & Databases

Ensembl (ENSG00000038002)NCBI Gene (175)OMIM (613228)HGNC:318GenCCUniProt (P20933)AlphaFoldClinVar (AGA)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

aspartylglucosaminuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: G2P

aspartylglucosaminuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: Genomics England PanelApp

aspartylglucosaminuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: ClinGen

The relationship between the AGA gene and aspartylglucosaminuria (AGU), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 7, 2022. AGA encodes aspartylglucosaminidase, an enzyme involved in the breakdown of N-linked oligosaccharides of glycoproteins via cleaving asparagine from the N-acetylglucosamine (PMID: 1703489). Individuals with AGU show deficient aspartylglucosaminidase enzyme activity, leading to accumulation of aspartylglucosamine and other glycoasparagines in multiple tissues and in the urine (PMID: 8405810, PMID: 27906067), which results in the characteristic disease manifestations including progressive neurological impairment and skeletal and connective tissue anomalies (as reviewed in PMID: 27906067). The disease mechanism of AGU is loss of function. AGU was first reported in 1967 by Jenner and Pollitt (Jenner, F. A., Pollitt, R. J. Large quantities of 2-acetamido-1-(beta-L-aspartamido)-1,2-dideoxyglucose in the urine of mentally retarded siblings. Biochem. J. 103: 48P-49P, 1967.) and 1968 by Pollitt et al. (PMID: 4173687) and the first reports of biallelic variants in AGA among cases with AGU in 1991 by Ikonen et al. (PMID: 1703489) and Fisher and Aronson (PMID: 1904874). Both case-level (genetic) and experimental evidence support the relationship between AGA and AGU. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 1703489, PMID: 1722323, PMID: 8830180, PMID: 7627186, PMID: 29247835, PMID: 11309371). In total, ten variants from eight probands in six publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between AGA and AGU includes: the biochemical function of the gene product (aspartylglucosaminidase) being consistent with the clinical and biochemical findings identified individuals with AGU (PMID: 8405810, PMID: 27906067); the biochemical and clinical features of AGA knockout mice (PMID: 8946839); and rescue of systemic accumulation of mannose N-linked oligosaccharides via enzyme replacement therapy in AGA knockout mice (PMID: 20607610). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, AGA is definitively associated with AGU. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).

aspartylglucosaminuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: Natera

aspartylglucosaminuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: PanelApp Australia

aspartylglucosaminuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: Labcorp Genetics (formerly Invitae)

aspartylglucosaminuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: Myriad Women's Health

aspartylglucosaminuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008830

Submitter: Orphanet

Clinical Genomic Database (CGD)

AspartylglucosaminuriaAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic

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: 4173687; 5512217; 6796777; 6883788; 3228136; 1904874; 1722323; 1703489; 1765378; 1756604; 1301945; 8405810; 8064811; 9427148; 9627765; 10353787; 11174635; 11796409; 12022293; 12366426; 15127757; 16218917; 23271757Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AGA variants in ClinVar

9 Conditions Cataloged
AspartylglucosaminuriaTotal: 503
not providedTotal: 61
not specifiedTotal: 33
Inborn genetic diseasesTotal: 31
AGA-related disorderTotal: 13
Intellectual disabilityTotal: 6
Neurodevelopmental disorderTotal: 1
AutismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000027.4. 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
5
clinvar
134
clinvar
 139
missense
6
clinvar
14
clinvar
119
clinvar
13
clinvar
 152
nonsense
9
clinvar
16
clinvar
2
clinvar
 27
start loss
1
clinvar
3
clinvar
 4
frameshift
20
clinvar
32
clinvar
4
clinvar
 56
splice donor/acceptor (+/-2bp)
4
clinvar
24
clinvar
1
clinvar
 29
Total40891311470407

Highest pathogenic variant AF is 0.00034640604

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000027.4RefSeqNP_000018.29MANE Select
ENST00000264595.7EnsemblENSP00000264595.29MANE Select
NM_001171988.2RefSeqNP_001165459.19Standard
ENST00000502310.5EnsemblENSP00000423798.15Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Other glycan degradation - Homo sapiens (human)
  • Neutrophil degranulation
  • Innate Immune System
  • Immune System

Biological Process

  • proteolysis
  • protein deglycosylation
  • neutrophil degranulation
  • protein maturation

Molecular Function

  • N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity
  • peptidase activity
  • hydrolase activity
  • protein self-association

Cellular Component

  • extracellular region
  • extracellular space
  • cytoplasm
  • lysosome
  • endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264595
Coding exons
9
Length
11734
Individuals with no LoFs
125698
Homozygous LoFs
0
Heterozygous LoFs
50
Defined
125748
p
0.000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.4452141961.090.00001022253
Missense (PolyPhen)7873.8821.0557813
Synonymous0.5006166.20.9220.00000346684
Loss of Function1.431117.40.6318.48e-7208

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish00.0absent
East Asian0.000220.00022rare
Finnish00.0absent
European (Non-Finnish)0.000230.00023rare
South Asian0.000130.00013rare
Other0.000650.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. {ECO:0000269|PubMed:1703489, ECO:0000269|PubMed:1904874, ECO:0000269|PubMed:2401370}.;
Disease
DISEASE: Aspartylglucosaminuria (AGU) [MIM:208400]: An inborn lysosomal storage disease causing excess accumulation of glycoasparagine in the body tissues and its increased excretion in urine. Clinical features include mild to severe mental retardation manifesting from the age of two, coarse facial features and mild connective tissue abnormalities. {ECO:0000269|PubMed:11309371, ECO:0000269|PubMed:1703489, ECO:0000269|PubMed:1904874, ECO:0000269|PubMed:2011603, ECO:0000269|PubMed:8776587, ECO:0000269|PubMed:9137882}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.220

Intolerance Scores

LoFtool
0.308
RVIS EVS
0.75
RVIS percentile EVS
86.71

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.532

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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