dbSNP rs121912591: NAGS:p.Ala279Thr (chr17-44006157-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_153006.3(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). Synonymous variant affecting the same amino acid position (i.e. A279A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NAGS
NM_153006.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.70

Publications

7 publications found

Variant links:

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]

NAGS Gene-Disease associations (from GenCC):

hyperammonemia due to N-acetylglutamate synthase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

NAGS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-44006157-G-A is Pathogenic according to our data. Variant chr17-44006157-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2431.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3 link	c.835G>A	p.Ala279Thr	missense_variant	Exon 3 of 7	ENST00000293404.8	NP_694551.1	Q8N159
NAGS	XM_011524438.2 link	c.835G>A	p.Ala279Thr	missense_variant	Exon 3 of 6		XP_011522740.1
NAGS	XM_011524439.2 link	c.337G>A	p.Ala113Thr	missense_variant	Exon 3 of 7		XP_011522741.1	Q2NKP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAGS	ENST00000293404.8 link	c.835G>A	p.Ala279Thr	missense_variant	Exon 3 of 7	1	NM_153006.3	ENSP00000293404.2	Q8N159
NAGS	ENST00000589767.1 link	c.742G>A	p.Ala248Thr	missense_variant	Exon 3 of 7	2		ENSP00000465408.1	K7EK11
NAGS	ENST00000592915.1 link	n.110G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

247788

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000364

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hyperammonemia, type III

Pathogenic:1

Aug 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

T;T

M_CAP

Uncertain

0.099

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.4

L;.

PhyloP100

2.7

PrimateAI

Uncertain

0.54

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

GERP RS

4.5

Varity_R

0.20

gMVP

0.85

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over