chr17-44004697-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153006.3(NAGS):​c.34G>C​(p.Ala12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000085 in 1,529,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

NAGS
NM_153006.3 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.0760
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]
PYY (HGNC:9748): (peptide YY) This gene encodes a member of the neuropeptide Y (NPY) family of peptides. The encoded preproprotein is proteolytically processed to generate two alternative peptide products that differ in length by three amino acids. These peptides, secreted by endocrine cells in the gut, exhibit different binding affinities for each of the neuropeptide Y receptors. Binding of the encoded peptides to these receptors mediates regulation of pancreatic secretion, gut mobility and energy homeostasis. Rare variations in this gene could increase susceptibility to obesity and elevated serum levels of the encoded peptides may be associated with anorexia nervosa. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NAGSNM_153006.3 linkc.34G>C p.Ala12Pro missense_variant Exon 1 of 7 ENST00000293404.8 NP_694551.1 Q8N159
NAGSXM_011524438.2 linkc.34G>C p.Ala12Pro missense_variant Exon 1 of 6 XP_011522740.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NAGSENST00000293404.8 linkc.34G>C p.Ala12Pro missense_variant Exon 1 of 7 1 NM_153006.3 ENSP00000293404.2 Q8N159
PYYENST00000360085.6 linkc.-769C>G upstream_gene_variant 1 ENSP00000353198.1 P10082-1
NAGSENST00000589767.1 linkc.-60G>C upstream_gene_variant 2 ENSP00000465408.1 K7EK11

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152258
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000871
AC:
12
AN:
1377034
Hom.:
0
Cov.:
31
AF XY:
0.00000877
AC XY:
6
AN XY:
683982
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000270
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000842
Gnomad4 OTH exome
AF:
0.0000178
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 08, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.34G>C (p.A12P) alteration is located in exon 1 (coding exon 1) of the NAGS gene. This alteration results from a G to C substitution at nucleotide position 34, causing the alanine (A) at amino acid position 12 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Apr 26, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The A12P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A12P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A12P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to)] the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hyperammonemia, type III Uncertain:1
Aug 13, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
14
DANN
Benign
0.96
DEOGEN2
Benign
0.32
T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.89
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.46
T
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.56
D
MetaSVM
Uncertain
0.061
D
MutationAssessor
Benign
0.69
N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.17
N
REVEL
Uncertain
0.48
Sift
Benign
0.051
T
Sift4G
Benign
0.076
T
Polyphen
0.61
P
Vest4
0.57
MVP
0.89
MPC
0.96
ClinPred
0.065
T
GERP RS
0.53
Varity_R
0.097
gMVP
0.56

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: rs759453873; hg19: chr17-42082065; API