chr17-44006699-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_153006.3(NAGS):c.1086T>C(p.Phe362Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,606,072 control chromosomes in the GnomAD database, including 29,553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2211 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27342 hom. )

Consequence

NAGS
NM_153006.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.614

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 17-44006699-T-C is Benign according to our data. Variant chr17-44006699-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 203863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.614 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3 link	c.1086T>C	p.Phe362Phe	synonymous_variant	Exon 4 of 7	ENST00000293404.8	NP_694551.1	Q8N159
NAGS	XM_011524438.2 link	c.1086T>C	p.Phe362Phe	synonymous_variant	Exon 4 of 6		XP_011522740.1
NAGS	XM_011524439.2 link	c.588T>C	p.Phe196Phe	synonymous_variant	Exon 4 of 7		XP_011522741.1	Q2NKP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAGS	ENST00000293404.8 link	c.1086T>C	p.Phe362Phe	synonymous_variant	Exon 4 of 7	1	NM_153006.3	ENSP00000293404.2	Q8N159
NAGS	ENST00000589767.1 link	c.993T>C	p.Phe331Phe	synonymous_variant	Exon 4 of 7	2		ENSP00000465408.1	K7EK11
NAGS	ENST00000592915.1 link	n.361T>C		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24404

AN:

152058

Hom.:

2210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.0125

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.157

AC:

37897

AN:

241090

AF XY:

0.158

show subpopulations

Gnomad AFR exome

AF:

0.0986

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.00565

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.199

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.188

AC:

273268

AN:

1453896

Hom.:

27342

Cov.:

AF XY:

0.186

AC XY:

133988

AN XY:

722116

show subpopulations

African (AFR)

AF:

0.0922

AC:

3077

AN:

33370

American (AMR)

AF:

0.124

AC:

5511

AN:

44466

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3832

AN:

25986

East Asian (EAS)

AF:

0.0165

AC:

654

AN:

39552

South Asian (SAS)

AF:

0.121

AC:

10415

AN:

85934

European-Finnish (FIN)

AF:

0.233

AC:

12103

AN:

52048

Middle Eastern (MID)

AF:

0.0853

AC:

452

AN:

5298

European-Non Finnish (NFE)

AF:

0.205

AC:

226937

AN:

1107242

Other (OTH)

AF:

0.171

AC:

10287

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

13291

26581

39872

53162

66453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7736

15472

23208

30944

38680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.160

AC:

24410

AN:

152176

Hom.:

2211

Cov.:

AF XY:

0.161

AC XY:

11946

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.100

AC:

4153

AN:

41534

American (AMR)

AF:

0.150

AC:

2290

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

504

AN:

3472

East Asian (EAS)

AF:

0.0124

AC:

AN:

5176

South Asian (SAS)

AF:

0.120

AC:

579

AN:

4826

European-Finnish (FIN)

AF:

0.248

AC:

2628

AN:

10588

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13680

AN:

67976

Other (OTH)

AF:

0.131

AC:

276

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1064

2128

3191

4255

5319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.178

Hom.:

1753

Bravo

AF:

0.146

Asia WGS

AF:

0.0540

AC:

187

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperammonemia, type III

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.61

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over