17-44007782-T-C

Variant summary

Our verdict is Benign. Variant got -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:8 O:1
• Conservation: PhyloP100: -1.80

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 262688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44007782-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGS	NM_153006.3	c.1451+9T>C		intron_variant		ENST00000293404.8
NAGS	XM_011524438.2	c.1268+288T>C		intron_variant
NAGS	XM_011524439.2	c.953+9T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGS	ENST00000293404.8	c.1451+9T>C		intron_variant		1	NM_153006.3	P1
NAGS	ENST00000589767.1	c.1382+9T>C		intron_variant		2
NAGS	ENST00000592915.1	n.1339+9T>C		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.953 AC: 179303 AN: 188228 Hom.: 85529 AF XY: 0.954 AC XY: 96584 AN XY: 101260

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 SAS exome AF: 0.984

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

Gnomad4 AFR exome AF: 0.899

Gnomad4 AMR exome AF: 0.969

Gnomad4 ASJ exome AF: 0.957

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.983

Gnomad4 FIN exome AF: 0.950

Gnomad4 NFE exome AF: 0.944

Gnomad4 OTH exome AF: 0.951

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

Gnomad4 AFR AF: 0.902

Gnomad4 AMR AF: 0.960

Gnomad4 ASJ AF: 0.958

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.989

Gnomad4 FIN AF: 0.950

Gnomad4 NFE AF: 0.941

Gnomad4 OTH AF: 0.952

Alfa AF: 0.941 Hom.: 23255

Bravo AF: 0.935

Asia WGS AF: 0.986 AC: 3428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperammonemia, type III Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.7
Dann	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs228773; hg19: chr17-42085150;