rs185863881

chr17-44005037-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:6 O:1
• Conservation: PhyloP100: 1.25

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 -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 submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=1}. Variant chr17-44005037-C-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGS	NM_153006.3	c.374C>A	p.Thr125Lys	missense_variant	1/7	ENST00000293404.8
NAGS	XM_011524438.2	c.374C>A	p.Thr125Lys	missense_variant	1/6
NAGS	XM_011524439.2	c.-347C>A		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGS	ENST00000293404.8	c.374C>A	p.Thr125Lys	missense_variant	1/7	1	NM_153006.3	P1
NAGS	ENST00000589767.1	c.281C>A	p.Thr94Lys	missense_variant	1/7	2

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

GnomAD3 exomes AF: 0.00272 AC: 480 AN: 176178 Hom.: 2 AF XY: 0.00318 AC XY: 309 AN XY: 97138

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 SAS exome AF: 0.00677

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

Gnomad4 AFR exome AF: 0.000671

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00102

Gnomad4 EAS exome AF: 0.0000796

Gnomad4 SAS exome AF: 0.00724

Gnomad4 FIN exome AF: 0.000249

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00359

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

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00248 Hom.: 1

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:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 18, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NAGS: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2017

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. -

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;.
MutationTaster	Benign	0.81	D
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
Varity_R		0.052
gMVP		0.49

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: rs185863881; hg19: chr17-42082405;