17-44004845-A-T

Variant names:

• chr17-44004845-A-T
• rs113134544
• NM_153006.3:c.182A>T

Variant summary

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

The NM_153006.3(NAGS):​c.182A>T​(p.Glu61Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E61G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NAGS NM_153006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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=0.3782284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.182A>T	p.Glu61Val	missense_variant	Exon 1 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.182A>T	p.Glu61Val	missense_variant	Exon 1 of 6		XP_011522740.1
NAGS	XM_011524439.2	c.-539A>T		upstream_gene_variant			XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.182A>T	p.Glu61Val	missense_variant	Exon 1 of 7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.89A>T	p.Glu30Val	missense_variant	Exon 1 of 7	2		ENSP00000465408.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000821 AC: 1 AN: 121760 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67048

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000423

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369792 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 674960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.97	L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.42	N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.057	T;D
Polyphen		0.077	B;.
Vest4		0.39
MutPred		0.23		Loss of solvent accessibility (P = 0.0022);.;
MVP		0.90
MPC		1.0
ClinPred		0.32	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.51

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: rs113134544; hg19: chr17-42082213;