17-44008604-C-T

Position:

chr17-44008604-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153006.3(NAGS):c.*3C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,478 control chromosomes in the GnomAD database, including 308,699 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23504 hom., cov: 34)

Exomes 𝑓: 0.62 ( 285195 hom. )

Consequence

NAGS
NM_153006.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.132

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:

NAGS (HGNC:):

NAGS links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-44008604-C-T is Benign according to our data. Variant chr17-44008604-C-T is described in ClinVar as [Benign]. Clinvar id is 262686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44008604-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
NAGS	NM_153006.3 linkuse as main transcript	c.*3C>T	3_prime_UTR_variant	7/7	ENST00000293404.8	NP_694551.1	Q8N159
NAGS	XM_011524438.2 linkuse as main transcript	c.*3C>T	3_prime_UTR_variant	6/6		XP_011522740.1
NAGS	XM_011524439.2 linkuse as main transcript	c.*3C>T	3_prime_UTR_variant	7/7		XP_011522741.1	Q2NKP2

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NAGS	ENST00000293404.8 linkuse as main transcript	c.*3C>T	3_prime_UTR_variant	7/7	1	NM_153006.3	ENSP00000293404.2	Q8N159
NAGS	ENST00000589767.1 linkuse as main transcript	c.*3C>T	3_prime_UTR_variant	7/7	2		ENSP00000465408.1	K7EK11
NAGS	ENST00000592915.1 linkuse as main transcript	n.1496C>T	non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.544

AC:

82636

AN:

152032

Hom.:

23505

Cov.:

show subpopulations

Gnomad AFR

AF:

0.410

Gnomad AMI

AF:

0.582

Gnomad AMR

AF:

0.493

Gnomad ASJ

AF:

0.675

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.600

Gnomad FIN

AF:

0.544

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.611

GnomAD3 exomes

AF:

0.561

AC:

141067

AN:

251416

Hom.:

41513

AF XY:

0.575

AC XY:

78090

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.408

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.670

Gnomad EAS exome

AF:

0.269

Gnomad SAS exome

AF:

0.605

Gnomad FIN exome

AF:

0.550

Gnomad NFE exome

AF:

0.648

Gnomad OTH exome

AF:

0.612

GnomAD4 exome

AF:

0.619

AC:

904040

AN:

1461328

Hom.:

285195

Cov.:

AF XY:

0.620

AC XY:

450711

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.406

Gnomad4 AMR exome

AF:

0.440

Gnomad4 ASJ exome

AF:

0.669

Gnomad4 EAS exome

AF:

0.260

Gnomad4 SAS exome

AF:

0.605

Gnomad4 FIN exome

AF:

0.558

Gnomad4 NFE exome

AF:

0.648

Gnomad4 OTH exome

AF:

0.602

GnomAD4 genome

AF:

0.543

AC:

82640

AN:

152150

Hom.:

23504

Cov.:

AF XY:

0.537

AC XY:

39952

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.409

Gnomad4 AMR

AF:

0.492

Gnomad4 ASJ

AF:

0.675

Gnomad4 EAS

AF:

0.257

Gnomad4 SAS

AF:

0.600

Gnomad4 FIN

AF:

0.544

Gnomad4 NFE

AF:

0.644

Gnomad4 OTH

AF:

0.611

Alfa

AF:

0.600

Hom.:

18394

Bravo

AF:

0.534

Asia WGS

AF:

0.462

AC:

1610

AN:

3478

EpiCase

AF:

0.656

EpiControl

AF:

0.653

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperammonemia, type III

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:3

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

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

DANN

Benign

0.55

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