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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.1451+9T>C		intron_variant	Intron 6 of 6	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.1268+288T>C		intron_variant	Intron 5 of 5		XP_011522740.1
NAGS	XM_011524439.2	c.953+9T>C		intron_variant	Intron 6 of 6		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.1451+9T>C		intron_variant	Intron 6 of 6	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.1382+9T>C		intron_variant	Intron 6 of 6	2		ENSP00000465408.1
NAGS	ENST00000592915.1	n.1339+9T>C		intron_variant	Intron 3 of 3	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

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

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperammonemia, type III Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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
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;