rs121912591

Positions:

• chr17-44006157-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The ENST00000293404.8(NAGS):​c.835G>A​(p.Ala279Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A279P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAGS ENST00000293404.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.70

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant 17-44006157-G-A is Pathogenic according to our data. Variant chr17-44006157-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2431.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGS	NM_153006.3	c.835G>A	p.Ala279Thr	missense_variant	3/7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.835G>A	p.Ala279Thr	missense_variant	3/6		XP_011522740.1
NAGS	XM_011524439.2	c.337G>A	p.Ala113Thr	missense_variant	3/7		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.835G>A	p.Ala279Thr	missense_variant	3/7	1	NM_153006.3	ENSP00000293404	P1
NAGS	ENST00000589767.1	c.742G>A	p.Ala248Thr	missense_variant	3/7	2		ENSP00000465408
NAGS	ENST00000592915.1	n.110G>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperammonemia, type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.78	A
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.82	N;.
REVEL	Uncertain	0.41
Sift	Benign	0.63	T;.
Sift4G	Benign	0.30	T;T
Polyphen		0.66	P;.
Vest4		0.39
MutPred		0.48		Gain of glycosylation at A279 (P = 0.0748);.;
MVP		0.95
MPC		0.92
ClinPred		0.78	D
GERP RS		4.5
Varity_R		0.20
gMVP		0.85

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: rs121912591; hg19: chr17-42083525;