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 VariationId is 377250.
• 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	NM_153006.3	MANE Select	c.374C>A	p.Thr125Lys	missense	Exon 1 of 7	NP_694551.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	ENST00000293404.8	TSL:1 MANE Select	c.374C>A	p.Thr125Lys	missense	Exon 1 of 7	ENSP00000293404.2
	NAGS	ENST00000589767.1	TSL:2	c.281C>A	p.Thr94Lys	missense	Exon 1 of 7	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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Hyperammonemia, type III (5)
-	-	2	not provided (2)
-	-	1	NAGS-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0079	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
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;