17-44005037-C-A

Position:

chr17-44005037-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_153006.3(NAGS):c.374C>A(p.Thr125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,569,814 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 12 hom. )

Consequence

NAGS
NM_153006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 1.25

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007922173).

BP6

Variant 17-44005037-C-A is Benign according to our data. Variant chr17-44005037-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=1}. Variant chr17-44005037-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00196 (299/152354) while in subpopulation SAS AF= 0.00517 (25/4834). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NAGS	NM_153006.3 linkuse as main transcript	c.374C>A	p.Thr125Lys	missense_variant	1/7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2 linkuse as main transcript	c.374C>A	p.Thr125Lys	missense_variant	1/6		XP_011522740.1
NAGS	XM_011524439.2 linkuse as main transcript	c.-347C>A		5_prime_UTR_variant	1/7		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8 linkuse as main transcript	c.374C>A	p.Thr125Lys	missense_variant	1/7	1	NM_153006.3	ENSP00000293404	P1
NAGS	ENST00000589767.1 linkuse as main transcript	c.281C>A	p.Thr94Lys	missense_variant	1/7	2		ENSP00000465408

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

299

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00272

AC:

480

AN:

176178

Hom.:

AF XY:

0.00318

AC XY:

309

AN XY:

97138

show subpopulations

Gnomad AFR exome

AF:

0.000417

Gnomad AMR exome

AF:

0.00222

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.000142

Gnomad SAS exome

AF:

0.00677

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00271

GnomAD4 exome

AF:

0.00355

AC:

5033

AN:

1417460

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

2613

AN XY:

702376

show subpopulations

Gnomad4 AFR exome

AF:

0.000671

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00102

Gnomad4 EAS exome

AF:

0.0000796

Gnomad4 SAS exome

AF:

0.00724

Gnomad4 FIN exome

AF:

0.000249

Gnomad4 NFE exome

AF:

0.00371

Gnomad4 OTH exome

AF:

0.00359

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152354

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00517

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00300

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00248

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000699

AC:

ESP6500EA

AF:

0.00202

AC:

ExAC

AF:

0.00182

AC:

216

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperammonemia, type III

Uncertain:1Benign:3Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 18, 2019	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NAGS: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2017

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. -

NAGS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

0.81

PrimateAI

Benign

0.34

PROVEAN

Benign

1.7

N;.

REVEL

Uncertain

0.35

Sift

Benign

1.0

T;.

Sift4G

Benign

0.76

T;T

Polyphen

0.36

B;.

Vest4

0.37

MVP

0.83

MPC

0.92

ClinPred

0.010

GERP RS

1.1

Varity_R

0.052

gMVP

0.49

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