rs150004962

Variant names:

• chr17-44007624-C-T
• rs150004962
• NM_153006.3:c.1302C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_153006.3(NAGS):​c.1302C>T​(p.Pro434Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,606,326 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: NAGS NM_153006.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -3.31
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-44007624-C-T is Benign according to our data. Variant chr17-44007624-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 323450.
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000742 (113/152348) while in subpopulation SAS AF = 0.00166 (8/4832). AF 95% confidence interval is 0.000994. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.1302C>T	p.Pro434Pro	synonymous	Exon 6 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.1302C>T	p.Pro434Pro	synonymous	Exon 6 of 7	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.1317C>T	p.Pro439Pro	synonymous	Exon 6 of 7	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.1233C>T	p.Pro411Pro	synonymous	Exon 6 of 7	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00101 AC: 232 AN: 229880 AF XY: 0.00112

Gnomad AFR exome AF: 0.000144

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.00118 AC: 1712 AN: 1453978 Hom.: 5 Cov.: 30 AF XY: 0.00122 AC XY: 882 AN XY: 722828

African (AFR) AF: 0.000270 AC: 9 AN: 33280

American (AMR) AF: 0.000161 AC: 7 AN: 43450

Ashkenazi Jewish (ASJ) AF: 0.000849 AC: 22 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.00236 AC: 201 AN: 85300

European-Finnish (FIN) AF: 0.000285 AC: 15 AN: 52560

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.00125 AC: 1383 AN: 1108484

Other (OTH) AF: 0.00122 AC: 73 AN: 59998

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74506

African (AFR) AF: 0.000216 AC: 9 AN: 41576

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000714

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Hyperammonemia, type III (4)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.4
DANN	Benign	0.93
PhyloP100		-3.3
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs150004962; hg19: chr17-42084992; COSMIC: COSV52813300; COSMIC: COSV52813300;