rs55708447

Positions:

chr17-44006699-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_153006.3(NAGS):c.1086T>C(p.Phe362=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 203863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44006699-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein
NAGS	NM_153006.3 linkuse as main transcript	c.1086T>C	p.Phe362=	synonymous_variant	4/7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2 linkuse as main transcript	c.1086T>C	p.Phe362=	synonymous_variant	4/6		XP_011522740.1
NAGS	XM_011524439.2 linkuse as main transcript	c.588T>C	p.Phe196=	synonymous_variant	4/7		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NAGS	ENST00000293404.8 linkuse as main transcript	c.1086T>C	p.Phe362=	synonymous_variant	4/7	1	NM_153006.3	ENSP00000293404	P1
NAGS	ENST00000589767.1 linkuse as main transcript	c.993T>C	p.Phe331=	synonymous_variant	4/7	2		ENSP00000465408
NAGS	ENST00000592915.1 linkuse as main transcript	n.361T>C		non_coding_transcript_exon_variant	2/4	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

GnomAD3 exomes

AF:

0.157

AC:

37897

AN:

241090

Hom.:

3476

AF XY:

0.158

AC XY:

20863

AN XY:

131760

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 SAS exome

AF:

0.118

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

Gnomad4 AFR exome

AF:

0.0922

Gnomad4 AMR exome

AF:

0.124

Gnomad4 ASJ exome

AF:

0.147

Gnomad4 EAS exome

AF:

0.0165

Gnomad4 SAS exome

AF:

0.121

Gnomad4 FIN exome

AF:

0.233

Gnomad4 NFE exome

AF:

0.205

Gnomad4 OTH exome

AF:

0.171

GnomAD4 genome

AF:

0.160

AC:

24410

AN:

152176

Hom.:

2211

Cov.:

AF XY:

0.161

AC XY:

11946

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.100

Gnomad4 AMR

AF:

0.150

Gnomad4 ASJ

AF:

0.145

Gnomad4 EAS

AF:

0.0124

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.248

Gnomad4 NFE

AF:

0.201

Gnomad4 OTH

AF:

0.131

Alfa

AF:

0.179

Hom.:

1418

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hyperammonemia, type III

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not provided

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over