chr17-44006729-C-G

Position:

• chr17-44006729-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153006.3(NAGS):​c.1096+20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,579,606 control chromosomes in the GnomAD database, including 130,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8719 hom., cov: 31)
  • Exomes 𝑓: 0.40 (121341 hom.)
• Consequence: NAGS NM_153006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.49

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-44006729-C-G is Benign according to our data. Variant chr17-44006729-C-G is described in ClinVar as [Benign]. Clinvar id is 262687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44006729-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGS	NM_153006.3	c.1096+20C>G		intron_variant		ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.1096+20C>G		intron_variant			XP_011522740.1
NAGS	XM_011524439.2	c.598+20C>G		intron_variant			XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.1096+20C>G		intron_variant		1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.1003+20C>G		intron_variant		2		ENSP00000465408.1
NAGS	ENST00000592915.1	n.391C>G		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44700 AN: 151908 Hom.: 8717 Cov.: 31

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.309 AC: 68129 AN: 220622 Hom.: 12796 AF XY: 0.324 AC XY: 39174 AN XY: 120932

Gnomad AFR exome AF: 0.0683

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.451

Gnomad EAS exome AF: 0.0167

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.432

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.398 AC: 568093 AN: 1427580 Hom.: 121341 Cov.: 36 AF XY: 0.396 AC XY: 279521 AN XY: 705122

Gnomad4 AFR exome AF: 0.0685

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.447

Gnomad4 EAS exome AF: 0.0106

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.442

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.294 AC: 44680 AN: 152026 Hom.: 8719 Cov.: 31 AF XY: 0.286 AC XY: 21242 AN XY: 74298

Gnomad4 AFR AF: 0.0779

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.364

Alfa AF: 0.299 Hom.: 1363

Bravo AF: 0.283

Asia WGS AF: 0.156 AC: 544 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

Hyperammonemia, type III Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	-0.87
CADD	Benign	0.024
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs228771; hg19: chr17-42084097; COSMIC: COSV52813394; COSMIC: COSV52813394;