rs185863881

Variant names:

• chr17-44005037-C-A
• rs185863881
• NM_153006.3:c.374C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153006.3(NAGS):​c.374C>A​(p.Thr125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,569,814 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T125P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (12 hom.)
• Consequence: NAGS NM_153006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 1.25
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007922173).
• BP6: Variant 17-44005037-C-A is Benign according to our data. Variant chr17-44005037-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377250.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00196 (299/152354) while in subpopulation SAS AF = 0.00517 (25/4834). AF 95% confidence interval is 0.00359. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.374C>A	p.Thr125Lys	missense_variant	Exon 1 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.374C>A	p.Thr125Lys	missense_variant	Exon 1 of 6		XP_011522740.1
NAGS	XM_011524439.2	c.-347C>A		5_prime_UTR_variant	Exon 1 of 7		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.374C>A	p.Thr125Lys	missense_variant	Exon 1 of 7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.281C>A	p.Thr94Lys	missense_variant	Exon 1 of 7	2		ENSP00000465408.1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00272 AC: 480 AN: 176178 AF XY: 0.00318

Gnomad AFR exome AF: 0.000417

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000142

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00271

GnomAD4 exome AF: 0.00355 AC: 5033 AN: 1417460 Hom.: 12 Cov.: 31 AF XY: 0.00372 AC XY: 2613 AN XY: 702376

African (AFR) AF: 0.000671 AC: 22 AN: 32764

American (AMR) AF: 0.00237 AC: 95 AN: 40054

Ashkenazi Jewish (ASJ) AF: 0.00102 AC: 26 AN: 25480

East Asian (EAS) AF: 0.0000796 AC: 3 AN: 37698

South Asian (SAS) AF: 0.00724 AC: 590 AN: 81532

European-Finnish (FIN) AF: 0.000249 AC: 10 AN: 40098

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5736

European-Non Finnish (NFE) AF: 0.00371 AC: 4066 AN: 1095098

Other (OTH) AF: 0.00359 AC: 212 AN: 59000

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74504

African (AFR) AF: 0.000673 AC: 28 AN: 41584

American (AMR) AF: 0.00189 AC: 29 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00247 Hom.: 2

Bravo AF: 0.00213

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000699 AC: 3

ESP6500EA AF: 0.00202 AC: 17

ExAC AF: 0.00182 AC: 216

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperammonemia, type III Uncertain:1 Benign:3 Other:1

Dec 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NAGS: BP4, BS2 -

not specified Benign:1

Dec 26, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

NAGS-related disorder Benign:1

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.7	N;.
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;.
Sift4G	Benign	0.76	T;T
Polyphen		0.36	B;.
Vest4		0.37
MVP		0.83
MPC		0.92
ClinPred		0.010	T
GERP RS		1.1
PromoterAI		-0.014	Neutral
Varity_R		0.052
gMVP		0.49
Mutation Taster		=90/10	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: rs185863881; hg19: chr17-42082405;