rs113134544

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153006.3(NAGS):ā€‹c.182A>Gā€‹(p.Glu61Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,521,874 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.012 ( 37 hom., cov: 31)
Exomes š‘“: 0.0015 ( 30 hom. )

Consequence

NAGS
NM_153006.3 missense

Scores

5
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.41
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005270213).
BP6
Variant 17-44004845-A-G is Benign according to our data. Variant chr17-44004845-A-G is described in ClinVar as [Benign]. Clinvar id is 203864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44004845-A-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1896/152084) while in subpopulation AFR AF= 0.0428 (1777/41494). AF 95% confidence interval is 0.0412. There are 37 homozygotes in gnomad4. There are 926 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NAGSNM_153006.3 linkuse as main transcriptc.182A>G p.Glu61Gly missense_variant 1/7 ENST00000293404.8 NP_694551.1 Q8N159
NAGSXM_011524438.2 linkuse as main transcriptc.182A>G p.Glu61Gly missense_variant 1/6 XP_011522740.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NAGSENST00000293404.8 linkuse as main transcriptc.182A>G p.Glu61Gly missense_variant 1/71 NM_153006.3 ENSP00000293404.2 Q8N159
NAGSENST00000589767.1 linkuse as main transcriptc.89A>G p.Glu30Gly missense_variant 1/72 ENSP00000465408.1 K7EK11

Frequencies

GnomAD3 genomes
AF:
0.0124
AC:
1892
AN:
151972
Hom.:
37
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0429
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00432
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000500
Gnomad OTH
AF:
0.00863
GnomAD3 exomes
AF:
0.00208
AC:
253
AN:
121760
Hom.:
5
AF XY:
0.00166
AC XY:
111
AN XY:
67048
show subpopulations
Gnomad AFR exome
AF:
0.0365
Gnomad AMR exome
AF:
0.00211
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000282
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000566
Gnomad OTH exome
AF:
0.00158
GnomAD4 exome
AF:
0.00146
AC:
1995
AN:
1369790
Hom.:
30
Cov.:
31
AF XY:
0.00132
AC XY:
889
AN XY:
674958
show subpopulations
Gnomad4 AFR exome
AF:
0.0452
Gnomad4 AMR exome
AF:
0.00268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000244
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000343
Gnomad4 OTH exome
AF:
0.00269
GnomAD4 genome
AF:
0.0125
AC:
1896
AN:
152084
Hom.:
37
Cov.:
31
AF XY:
0.0125
AC XY:
926
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.0428
Gnomad4 AMR
AF:
0.00432
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000500
Gnomad4 OTH
AF:
0.00854
Alfa
AF:
0.00701
Hom.:
3
Bravo
AF:
0.0147
ESP6500AA
AF:
0.00663
AC:
14
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000757
AC:
27

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hyperammonemia, type III Benign:4
Likely benign, no assertion criteria providedclinical testingElsea Laboratory, Baylor College of MedicineApr 01, 2020- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 providedclinical testingNatera, Inc.Dec 05, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 17, 2018- -
Benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 05, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;.
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.43
T;T
MetaRNN
Benign
0.0053
T;T
MetaSVM
Uncertain
0.31
D
MutationAssessor
Benign
0.97
L;.
MutationTaster
Benign
0.93
N
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.32
N;.
REVEL
Benign
0.26
Sift
Uncertain
0.0040
D;.
Sift4G
Benign
0.30
T;D
Polyphen
0.023
B;.
Vest4
0.28
MVP
0.93
MPC
0.98
ClinPred
0.024
T
GERP RS
4.0
Varity_R
0.090
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113134544; hg19: chr17-42082213; API