rs146451392

Variant names:

• chr17-44006266-C-T
• rs146451392
• NM_153006.3:c.915+29C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44006266-C-T
• chr17-44006266-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153006.3(NAGS):​c.915+29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,608,426 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (134 hom.)
• Consequence: NAGS NM_153006.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.257
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-44006266-C-T is Benign according to our data. Variant chr17-44006266-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0097 (1477/152336) while in subpopulation NFE AF = 0.0114 (778/68028). AF 95% confidence interval is 0.0108. There are 14 homozygotes in GnomAd4. There are 790 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.915+29C>T		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.915+29C>T		intron	N/A	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.930+29C>T		intron	N/A	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.822+29C>T		intron	N/A	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1477 AN: 152218 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00904 AC: 2104 AN: 232808 AF XY: 0.00900

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0367

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00642

GnomAD4 exome AF: 0.0106 AC: 15500 AN: 1456090 Hom.: 134 Cov.: 32 AF XY: 0.0103 AC XY: 7488 AN XY: 724196

African (AFR) AF: 0.00138 AC: 46 AN: 33388

American (AMR) AF: 0.00355 AC: 157 AN: 44166

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 186 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85580

European-Finnish (FIN) AF: 0.0331 AC: 1718 AN: 51934

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.0116 AC: 12879 AN: 1109554

Other (OTH) AF: 0.00849 AC: 511 AN: 60166

GnomAD4 genome AF: 0.00970 AC: 1477 AN: 152336 Hom.: 14 Cov.: 32 AF XY: 0.0106 AC XY: 790 AN XY: 74494

African (AFR) AF: 0.00221 AC: 92 AN: 41584

American (AMR) AF: 0.0101 AC: 155 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0389 AC: 413 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0114 AC: 778 AN: 68028

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00827 Hom.: 0

Bravo AF: 0.00695

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.1
DANN	Benign	0.84
PhyloP100		-0.26
Mutation Taster		=100/0	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

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

Other links and lift over

dbSNP: rs146451392;

hg19: chr17-42083634;