chr17-44004671-C-G

Position:

• chr17-44004671-C-G

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]

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/exons	MANE	Protein	UniProt
NAGS	NM_153006.3	c.8C>G	p.Thr3Arg	missense_variant	1/7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.8C>G	p.Thr3Arg	missense_variant	1/6		XP_011522740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.8C>G	p.Thr3Arg	missense_variant	1/7	1	NM_153006.3	ENSP00000293404.2

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 14, 2020

- -

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
MutationTaster	Benign	0.79	N
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;