rs104894604

Variant names:

• chr17-44006584-G-A
• rs104894604
• NM_153006.3:c.971G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_153006.3(NAGS):​c.971G>A​(p.Trp324*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAGS NM_153006.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86
• Publications: 8 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44006584-G-A is Pathogenic according to our data. Variant chr17-44006584-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2428.Status of the report is no_assertion_criteria_provided, 0 stars.

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.971G>A	p.Trp324*	stop_gained	Exon 4 of 7	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.971G>A	p.Trp324*	stop_gained	Exon 4 of 7	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.986G>A	p.Trp329*	stop_gained	Exon 4 of 7	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.878G>A	p.Trp293*	stop_gained	Exon 4 of 7	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1439140 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 714046

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 41360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 38710

South Asian (SAS) AF: 0.00 AC: 0 AN: 83514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100316

Other (OTH) AF: 0.00 AC: 0 AN: 59478

GnomAD4 genome Cov.: 33

Alfa AF: 0.000144 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperammonemia, type III (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.9
Vest4		0.90
GERP RS		5.2
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 1

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

Other links and lift over

dbSNP: rs104894604; hg19: chr17-42083952;