chr17-44006729-C-G

Variant names:

• chr17-44006729-C-G
• rs228771
• NM_153006.3:c.1096+20C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 262687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.1096+20C>G		intron_variant	Intron 4 of 6	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.1096+20C>G		intron_variant	Intron 4 of 5		XP_011522740.1
NAGS	XM_011524439.2	c.598+20C>G		intron_variant	Intron 4 of 6		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.1096+20C>G		intron_variant	Intron 4 of 6	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000592915.1	n.391C>G		non_coding_transcript_exon_variant	Exon 2 of 4	2
NAGS	ENST00000589767.1	c.1003+20C>G		intron_variant	Intron 4 of 6	2		ENSP00000465408.1

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

GnomAD2 exomes AF: 0.309 AC: 68129 AN: 220622 AF XY: 0.324

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 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

African (AFR) AF: 0.0685 AC: 2264 AN: 33052

American (AMR) AF: 0.207 AC: 9028 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11144 AN: 24918

East Asian (EAS) AF: 0.0106 AC: 415 AN: 39176

South Asian (SAS) AF: 0.274 AC: 22864 AN: 83314

European-Finnish (FIN) AF: 0.322 AC: 15959 AN: 49638

Middle Eastern (MID) AF: 0.494 AC: 2202 AN: 4456

European-Non Finnish (NFE) AF: 0.442 AC: 482415 AN: 1090680

Other (OTH) AF: 0.371 AC: 21802 AN: 58768

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

African (AFR) AF: 0.0779 AC: 3232 AN: 41494

American (AMR) AF: 0.277 AC: 4232 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3468

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5166

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4822

European-Finnish (FIN) AF: 0.311 AC: 3287 AN: 10570

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29706 AN: 67928

Other (OTH) AF: 0.364 AC: 767 AN: 2106

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

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperammonemia, type III Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.024
DANN	Benign	0.61
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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