chr17-44004708-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_153006.3(NAGS):c.46del(p.Ala16ProfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
NAGS
NM_153006.3 frameshift
NM_153006.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.62
Genes affected
NAGS (HGNC:17996): (N-acetylglutamate synthase) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-44004708-AG-A is Pathogenic according to our data. Variant chr17-44004708-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 1445775.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGS | NM_153006.3 | c.46del | p.Ala16ProfsTer4 | frameshift_variant | 1/7 | ENST00000293404.8 | |
NAGS | XM_011524438.2 | c.46del | p.Ala16ProfsTer4 | frameshift_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGS | ENST00000293404.8 | c.46del | p.Ala16ProfsTer4 | frameshift_variant | 1/7 | 1 | NM_153006.3 | P1 | |
NAGS | ENST00000589767.1 | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hyperammonemia, type III Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 02, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with NAGS-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala16Profs*4) in the NAGS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAGS are known to be pathogenic (PMID: 12594532). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.