NAGS

N-acetylglutamate synthase, the group of GCN5 related N-acetyltransferases

Basic information

Region (hg38): 17:44004622-44009068

Links

ENSG00000161653 ∙ NCBI:162417 ∙ OMIM:608300 ∙ HGNC:17996 ∙ Uniprot:Q8N159 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyperammonemia due to N-acetylglutamate synthase deficiency (Definitive), mode of inheritance: AR
• hyperammonemia due to N-acetylglutamate synthase deficiency (Strong), mode of inheritance: AR
• hyperammonemia due to N-acetylglutamate synthase deficiency (Supportive), mode of inheritance: AR
• hyperammonemia due to N-acetylglutamate synthase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
N-acetylglutamate synthase deficiency	AR	Biochemical	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	Biochemical; Neurologic	7453791; 3139931; 2373115; 1405478; 7623444; 9877039; 10626533; 12594532; 17421020; 17510757; 19533169; 20301396; 21941437; 22594780; 23776373; 25135652

ClinVar

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

• Hyperammonemia, type III (36 variants)
• Inborn genetic diseases (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NAGS 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	270	2	274
missense		2	100	3	1	106
nonsense	10	16				26
start loss			1			1
frameshift	22	12				34
inframe indel						0
splice donor/acceptor (+/-2bp)	4	12				16
splice region		2	1	21		24
non coding			5	63	15	83
Total	36	42	108	336	18

Highest pathogenic variant AF is 0.0000131

Variants in NAGS

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

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

Position	Type	Phenotype	Significance	ClinVar
17-44004646-C-T		not specified	Likely benign (Apr 21, 2017)
17-44004657-TGTC-T			Uncertain significance (Aug 09, 2018)
17-44004665-T-C		Hyperammonemia, type III	Uncertain significance (Oct 17, 2022)
17-44004669-G-A		Hyperammonemia, type III	Likely benign (Nov 01, 2022)
17-44004671-C-G		Hyperammonemia, type III	Uncertain significance (Aug 14, 2020)
17-44004671-C-T		Hyperammonemia, type III	Uncertain significance (Jan 13, 2018)
17-44004672-G-A		Hyperammonemia, type III	Likely benign (Oct 07, 2022)
17-44004672-G-T		Hyperammonemia, type III	Likely benign (Jan 14, 2023)
17-44004678-G-A		Hyperammonemia, type III	Likely benign (Mar 01, 2023)
17-44004687-G-C		Hyperammonemia, type III	Likely benign (Jun 14, 2023)
17-44004688-G-A		Hyperammonemia, type III	Uncertain significance (Aug 13, 2020)
17-44004693-G-C		Hyperammonemia, type III	Likely benign (Jan 10, 2024)
17-44004694-CG-C		Hyperammonemia, type III	Pathogenic (Feb 08, 2019)
17-44004695-G-A		Hyperammonemia, type III	Uncertain significance (Dec 09, 2023)
17-44004697-G-A		Hyperammonemia, type III • Inborn genetic diseases	Uncertain significance (Dec 13, 2023)
17-44004697-G-C		Hyperammonemia, type III	Uncertain significance (Apr 26, 2017)
17-44004705-T-C		Hyperammonemia, type III	Likely benign (Nov 06, 2023)
17-44004708-A-C		Hyperammonemia, type III	Likely benign (Oct 31, 2023)
17-44004708-AG-A		Hyperammonemia, type III	Pathogenic (May 02, 2021)
17-44004714-G-A		Hyperammonemia, type III	Likely benign (Aug 02, 2023)
17-44004717-G-A		Hyperammonemia, type III	Likely benign (Jan 25, 2024)
17-44004719-T-C		Hyperammonemia, type III	Uncertain significance (Nov 18, 2023)
17-44004726-C-A		Hyperammonemia, type III	Likely benign (Apr 03, 2023)
17-44004726-C-G		Hyperammonemia, type III	Likely benign (May 05, 2021)
17-44004727-C-T		Hyperammonemia, type III • Inborn genetic diseases	Uncertain significance (Dec 27, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NAGS	protein_coding	protein_coding	ENST00000293404	7	4518

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.03e-8	0.586	125714	0	34	125748	0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.34	223	287	0.778	0.0000134	3341
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000156	0.000152
Ashkenazi Jewish	0.000612	0.000595
East Asian	0.000119	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000199	0.000185
Middle Eastern	0.000119	0.000109
South Asian	0.0000347	0.0000327
Other	0.000166	0.000163

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Arginine biosynthesis - Homo sapiens (human);Urea cycle and metabolism of amino groups;Metabolism of polyamines;Metabolism of amino acids and derivatives;Metabolism;Methionine and cysteine metabolism;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Glycine, serine, alanine and threonine metabolism;Urea cycle (Consensus)

Recessive Scores

• pRec: 0.269

Intolerance Scores

• loftool: 0.216
• rvis_EVS: -0.34
• rvis_percentile_EVS: 30.07

Haploinsufficiency Scores

• pHI: 0.139
• hipred: N
• hipred_score: 0.409
• ghis: 0.401

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.842

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nags
• Phenotype: growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: urea cycle;arginine biosynthetic process;glutamate metabolic process;phosphorylation
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: acetylglutamate kinase activity;acetyl-CoA:L-glutamate N-acetyltransferase activity;arginine binding;methione N-acyltransferase activity