NM_153006.3:c.*3C>T

Variant names:

• chr17-44008604-C-T
• rs186636
• NM_153006.3:c.*3C>T

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.*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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.132
• Publications: 24 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 -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 VariationId is 262686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.639 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.*3C>T		3_prime_UTR	Exon 7 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.*3C>T		3_prime_UTR	Exon 7 of 7	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.*3C>T		3_prime_UTR	Exon 7 of 7	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.*3C>T		3_prime_UTR	Exon 7 of 7	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82636 AN: 152032 Hom.: 23505 Cov.: 34

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

GnomAD2 exomes AF: 0.561 AC: 141067 AN: 251416 AF XY: 0.575

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 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.: 63 AF XY: 0.620 AC XY: 450711 AN XY: 726988

African (AFR) AF: 0.406 AC: 13580 AN: 33462

American (AMR) AF: 0.440 AC: 19677 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 17481 AN: 26132

East Asian (EAS) AF: 0.260 AC: 10331 AN: 39698

South Asian (SAS) AF: 0.605 AC: 52173 AN: 86228

European-Finnish (FIN) AF: 0.558 AC: 29815 AN: 53412

Middle Eastern (MID) AF: 0.700 AC: 3786 AN: 5412

European-Non Finnish (NFE) AF: 0.648 AC: 720881 AN: 1111918

Other (OTH) AF: 0.602 AC: 36316 AN: 60344

GnomAD4 genome AF: 0.543 AC: 82640 AN: 152150 Hom.: 23504 Cov.: 34 AF XY: 0.537 AC XY: 39952 AN XY: 74378

African (AFR) AF: 0.409 AC: 16987 AN: 41518

American (AMR) AF: 0.492 AC: 7518 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2345 AN: 3472

East Asian (EAS) AF: 0.257 AC: 1333 AN: 5182

South Asian (SAS) AF: 0.600 AC: 2896 AN: 4830

European-Finnish (FIN) AF: 0.544 AC: 5752 AN: 10582

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43761 AN: 67966

Other (OTH) AF: 0.611 AC: 1292 AN: 2116

Alfa AF: 0.601 Hom.: 20475

Bravo AF: 0.534

Asia WGS AF: 0.462 AC: 1610 AN: 3478

EpiCase AF: 0.656

EpiControl AF: 0.653

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hyperammonemia, type III (4)
-	-	3	not specified (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.55
PhyloP100		-0.13
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: rs186636; hg19: chr17-42085972; COSMIC: COSV52813006; COSMIC: COSV52813006;