17-44008604-C-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: 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=-0.84).
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.*3C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.*3C>T		3_prime_UTR_variant	Exon 6 of 6		XP_011522740.1
NAGS	XM_011524439.2	c.*3C>T		3_prime_UTR_variant	Exon 7 of 7		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.*3C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000592915.1	n.1496C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2
NAGS	ENST00000589767.1	c.*3C>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000465408.1

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

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperammonemia, type III Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

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	-0.84
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;