17-44004688-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153006.3(NAGS):c.25G>A(p.Val9Ile) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAGS NM_153006.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.34

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1226123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGS	NM_153006.3	c.25G>A	p.Val9Ile	missense_variant	1/7	ENST00000293404.8
NAGS	XM_011524438.2	c.25G>A	p.Val9Ile	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGS	ENST00000293404.8	c.25G>A	p.Val9Ile	missense_variant	1/7	1	NM_153006.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1381494 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686428

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.16
Sift	Benign	0.065	T
Sift4G	Benign	0.25	T
Polyphen		0.0080	B
Vest4		0.20
MutPred		0.32		Loss of disorder (P = 0.1722);
MVP		0.74
MPC		0.60
ClinPred		0.092	T
GERP RS		-0.028
Varity_R		0.054
gMVP		0.17

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: rs2049059364; hg19: chr17-42082056;