rs958791517

Variant names:

• chr17-44004671-C-G
• rs958791517
• NM_153006.3:c.8C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-44004671-C-G
• chr17-44004671-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153006.3(NAGS):​c.8C>G​(p.Thr3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAGS NM_153006.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.855

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33659855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.8C>G	p.Thr3Arg	missense_variant	Exon 1 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.8C>G	p.Thr3Arg	missense_variant	Exon 1 of 6		XP_011522740.1
PYY	NM_004160.6	c.-743G>C		upstream_gene_variant			NP_004151.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.8C>G	p.Thr3Arg	missense_variant	Exon 1 of 7	1	NM_153006.3	ENSP00000293404.2
PYY	ENST00000360085.6	c.-743G>C		upstream_gene_variant		1		ENSP00000353198.1
NAGS	ENST00000589767.1	c.-86C>G		upstream_gene_variant		2		ENSP00000465408.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperammonemia, type III Uncertain:1

Aug 14, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.97	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.37	B
Vest4		0.40
MutPred		0.31		Gain of methylation at T3 (P = 0.0081);
MVP		0.96
MPC		0.85
ClinPred		0.41	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.55

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: rs958791517; hg19: chr17-42082039;