chr17-44004708-AG-A

Position:

• chr17-44004708-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_153006.3(NAGS):​c.46delG​(p.Ala16fs) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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 21 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	Protein	UniProt
NAGS	NM_153006.3	c.46delG	p.Ala16fs	frameshift_variant	1/7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.46delG	p.Ala16fs	frameshift_variant	1/6		XP_011522740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.46delG	p.Ala16fs	frameshift_variant	1/7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.-48delG		upstream_gene_variant		2		ENSP00000465408.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperammonemia, type III Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42082076;