17-44007772-TGG-CGT

Variant names:

• chr17-44007772-TGG-CGT
• NM_153006.3:c.1450_1451+1delTGGinsCGT
• NAGS p.Trp484Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_153006.3(NAGS):​c.1450_1451+1delTGGinsCGT​(p.Trp484Arg) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAGS NM_153006.3 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.65
• Publications: 0 publications found

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]

NAGS Gene-Disease associations (from GenCC):

• hyperammonemia due to N-acetylglutamate synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11401869 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	NM_153006.3	MANE Select	c.1450_1451+1delTGGinsCGT	p.Trp484Arg	splice_donor missense splice_region intron	N/A	NP_694551.1	Q8N159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	ENST00000293404.8	TSL:1 MANE Select	c.1450_1451+1delTGGinsCGT	p.Trp484Arg	splice_donor missense splice_region intron	N/A	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.1465_1466+1delTGGinsCGT	p.Trp489Arg	splice_donor missense splice_region intron	N/A	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.1381_1382+1delTGGinsCGT	p.Trp461Arg	splice_donor missense splice_region intron	N/A	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-42085140;