chr17-44007621-G-C

Variant names:

• chr17-44007621-G-C
• rs104894607
• NM_153006.3:c.1299G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_153006.3(NAGS):​c.1299G>C​(p.Glu433Asp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E433E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAGS NM_153006.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.67
• Publications: 5 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_153006.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 17-44007621-G-C is Pathogenic according to our data. Variant chr17-44007621-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2434.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	c.1299G>C	p.Glu433Asp	missense_variant	Exon 6 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524439.2	c.801G>C	p.Glu267Asp	missense_variant	Exon 6 of 7		XP_011522741.1
NAGS	XM_011524438.2	c.1268+127G>C		intron_variant	Intron 5 of 5		XP_011522740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.1299G>C	p.Glu433Asp	missense_variant	Exon 6 of 7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.1230G>C	p.Glu410Asp	missense_variant	Exon 6 of 7	2		ENSP00000465408.1
NAGS	ENST00000592915.1	n.1187G>C		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		2.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.41
Sift	Benign	0.12	T;.
Sift4G	Benign	0.10	T;T
Vest4		0.89
ClinPred		0.82	D
GERP RS		0.81
Varity_R		0.71
gMVP		0.78
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894607; hg19: chr17-42084989;