chr17-44006699-T-C

Variant names:

• chr17-44006699-T-C
• rs55708447
• NM_153006.3:c.1086T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153006.3(NAGS):​c.1086T>C​(p.Phe362Phe) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.614
• Publications: 11 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 203863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	NM_153006.3	MANE Select	c.1086T>C	p.Phe362Phe	synonymous	Exon 4 of 7	NP_694551.1	Q8N159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	ENST00000293404.8	TSL:1 MANE Select	c.1086T>C	p.Phe362Phe	synonymous	Exon 4 of 7	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.1101T>C	p.Phe367Phe	synonymous	Exon 4 of 7	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.993T>C	p.Phe331Phe	synonymous	Exon 4 of 7	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24404 AN: 152058 Hom.: 2210 Cov.: 32

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

GnomAD2 exomes AF: 0.157 AC: 37897 AN: 241090 AF XY: 0.158

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 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.: 43 AF XY: 0.186 AC XY: 133988 AN XY: 722116

African (AFR) AF: 0.0922 AC: 3077 AN: 33370

American (AMR) AF: 0.124 AC: 5511 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3832 AN: 25986

East Asian (EAS) AF: 0.0165 AC: 654 AN: 39552

South Asian (SAS) AF: 0.121 AC: 10415 AN: 85934

European-Finnish (FIN) AF: 0.233 AC: 12103 AN: 52048

Middle Eastern (MID) AF: 0.0853 AC: 452 AN: 5298

European-Non Finnish (NFE) AF: 0.205 AC: 226937 AN: 1107242

Other (OTH) AF: 0.171 AC: 10287 AN: 60000

GnomAD4 genome AF: 0.160 AC: 24410 AN: 152176 Hom.: 2211 Cov.: 32 AF XY: 0.161 AC XY: 11946 AN XY: 74384

African (AFR) AF: 0.100 AC: 4153 AN: 41534

American (AMR) AF: 0.150 AC: 2290 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 504 AN: 3472

East Asian (EAS) AF: 0.0124 AC: 64 AN: 5176

South Asian (SAS) AF: 0.120 AC: 579 AN: 4826

European-Finnish (FIN) AF: 0.248 AC: 2628 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13680 AN: 67976

Other (OTH) AF: 0.131 AC: 276 AN: 2112

Alfa AF: 0.178 Hom.: 1753

Bravo AF: 0.146

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hyperammonemia, type III (4)
-	-	4	not specified (4)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.61
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: rs55708447; hg19: chr17-42084067; COSMIC: COSV52814386; COSMIC: COSV52814386;