NAGS
protein-codingN-acetylglutamate synthase, the group of GCN5 related N-acetyltransferases
Gene summary
The N-acetylglutamate synthase gene encodes a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme-A. NAG is a cofactor of carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle in mammals. This gene may regulate ureagenesis by altering NAG availability and, thereby, CPSI activity. Deficiencies in N-acetylglutamate synthase have been associated with hyperammonemia. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009377
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009377
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009377
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009377
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009377
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009377
Submitter: ClinGen
The relationship between NAGS and hyperammonemia due to N-acetylglutamate synthase deficiency, an autosomal recessive urea cycle disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 23, 2019. Variants in NAGS were first reported in patients with hyperammonemia in 2002 (Elpeleg et al, PMID 12447942). Data from 12 patients with 15 unique variants (missense, nonsense, frameshift, splicing) from 5 publications were curated (Elpeleg et al, 2002, PMID 12447942; Caldovic et al, 2003, PMID 12594532; Häberle et al, PMID 12754705; Caldovic et al, 2005, PMID 15714518; Sancho-Vaello et al, 2016, PMID 27037498). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between NAGS and hyperammonemia due to N-acetylglutamate synthase deficiency is supported by experimental evidence including the biochemical function of NAGS, which is consistent with the disease phenotype (Shigesada et al, 1971, PMID 5160402), the knowledge that N-acetylglutamate is a cofactor for carbamoyl phosphate synthase, which catalyzes the first step of the urea cycle and has been implicated hyperammonemia (Rubio et al, 1983, PMID 6223815), and the clinical and biochemical phenotype of a null mouse model (Senkevitch et al, 2012, PMID 22503289). In summary, NAGS is definitively associated with hyperammonemia due to N-acetylglutamate synthase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: The condition may manifest with severe neurological sequelae secondary to the accumulation of ammonia, and medical treatment both in the acute and chronic setting (eg, with N-carabamylglutamate) can be effective
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NAGS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_153006.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 290 | 3 | 299 | ||
| missense | 3 | 10 | 157 | 8 | 2 | 180 |
| nonsense | 10 | 22 | 32 | |||
| start loss | 1 | 1 | ||||
| frameshift | 23 | 26 | 49 | |||
| splice donor/acceptor (+/-2bp) | 4 | 17 | 1 | 22 | ||
| Total | 40 | 75 | 165 | 298 | 5 | 583 |
Highest pathogenic variant AF is 0.0000848766
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_694551.1 | 7 | MANE Select | |
| Ensembl | ENSP00000293404.2 | 7 | MANE Select | |
| Ensembl | ENSP00000465408.1 | 7 | Standard | |
| Ensembl | ENSP00000577036.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Arginine biosynthesis - Homo sapiens (human)
- Urea cycle and metabolism of amino groups
- Metabolism of polyamines
- Metabolism of amino acids and derivatives
- Metabolism
Biological Process
- urea cycle
- arginine biosynthetic process
- glutamate metabolic process
- phosphorylation
Molecular Function
- acetylglutamate kinase activity
- acetyl-CoA:L-glutamate N-acetyltransferase activity
- arginine binding
- methione N-acyltransferase activity
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000293404
- Coding exons
- 7
- Length
- 4518
- Individuals with no LoFs
- 125714
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 34
- Defined
- 125748
- p
- 0.000135
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.34 | 223 | 287 | 0.778 | 0.0000134 | 3341 |
| Missense (PolyPhen) | 56 | 93.548 | 0.59862 | 1158 | ||
| Synonymous | 0.00856 | 134 | 134 | 0.999 | 0.00000662 | 1157 |
| Loss of Function | 1.10 | 14 | 19.2 | 0.730 | 8.36e-7 | 196 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.00061 | 0.00060 | rare |
| East Asian | 0.00012 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00020 | 0.00018 | rare |
| South Asian | 0.000035 | 0.000033 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in the regulation of ureagenesis by producing the essential cofactor N-acetylglutamate (NAG), thus modulating carbamoylphosphate synthase I (CPS1) activity. {ECO:0000269|PubMed:12459178, ECO:0000269|PubMed:23894642, ECO:0000269|PubMed:7126172}.;
- Disease
- DISEASE: N-acetylglutamate synthase deficiency (NAGSD) [MIM:237310]: Rare autosomal recessively inherited metabolic disorder leading to severe neonatal or late-onset hyperammonemia without increased excretion of orotic acid. Clinical symptoms are somnolence, tachypnea, feeding difficulties, a severe neurologic presentation characterized by uncontrollable movements, developmental delay, visual impairment, failure to thrive and hyperammonemia precipitated by the introduction of high-protein diet or febrile illness. {ECO:0000269|PubMed:12754705, ECO:0000269|PubMed:15878741, ECO:0000269|PubMed:27037498}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.269
Intolerance Scores
- LoFtool
- 0.216
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.07
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.842
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |