17-44007782-T-C

Variant names:

• chr17-44007782-T-C
• rs228773
• NM_153006.3:c.1451+9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153006.3(NAGS):​c.1451+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.947 in 1,573,136 control chromosomes in the GnomAD database, including 705,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (66786 hom., cov: 29)
  • Exomes 𝑓: 0.95 (638974 hom.)
• Consequence: NAGS NM_153006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.80
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-44007782-T-C is Benign according to our data. Variant chr17-44007782-T-C is described in ClinVar as Benign. ClinVar VariationId is 262688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.1451+9T>C		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.1451+9T>C		intron	N/A	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.1466+9T>C		intron	N/A	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.1382+9T>C		intron	N/A	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142319 AN: 151900 Hom.: 66729 Cov.: 29

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.960

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.951

GnomAD2 exomes AF: 0.953 AC: 179303 AN: 188228 AF XY: 0.954

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.970

Gnomad ASJ exome AF: 0.951

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.948

Gnomad NFE exome AF: 0.936

Gnomad OTH exome AF: 0.950

GnomAD4 exome AF: 0.948 AC: 1347357 AN: 1421118 Hom.: 638974 Cov.: 51 AF XY: 0.949 AC XY: 667430 AN XY: 703242

African (AFR) AF: 0.899 AC: 28915 AN: 32156

American (AMR) AF: 0.969 AC: 39901 AN: 41174

Ashkenazi Jewish (ASJ) AF: 0.957 AC: 24345 AN: 25436

East Asian (EAS) AF: 1.00 AC: 37020 AN: 37028

South Asian (SAS) AF: 0.983 AC: 79440 AN: 80778

European-Finnish (FIN) AF: 0.950 AC: 47822 AN: 50360

Middle Eastern (MID) AF: 0.959 AC: 5291 AN: 5518

European-Non Finnish (NFE) AF: 0.944 AC: 1028722 AN: 1089896

Other (OTH) AF: 0.951 AC: 55901 AN: 58772

GnomAD4 genome AF: 0.937 AC: 142434 AN: 152018 Hom.: 66786 Cov.: 29 AF XY: 0.940 AC XY: 69848 AN XY: 74308

African (AFR) AF: 0.902 AC: 37407 AN: 41456

American (AMR) AF: 0.960 AC: 14680 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3324 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5120 AN: 5124

South Asian (SAS) AF: 0.989 AC: 4765 AN: 4820

European-Finnish (FIN) AF: 0.950 AC: 10058 AN: 10590

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 63962 AN: 67960

Other (OTH) AF: 0.952 AC: 2006 AN: 2108

Alfa AF: 0.940 Hom.: 32829

Bravo AF: 0.935

Asia WGS AF: 0.986 AC: 3428 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.7
DANN	Benign	0.72
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs228773; hg19: chr17-42085150;