rs55708447

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 203863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44006699-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.1086T>C	p.Phe362Phe	synonymous_variant	Exon 4 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524438.2	c.1086T>C	p.Phe362Phe	synonymous_variant	Exon 4 of 6		XP_011522740.1
NAGS	XM_011524439.2	c.588T>C	p.Phe196Phe	synonymous_variant	Exon 4 of 7		XP_011522741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.1086T>C	p.Phe362Phe	synonymous_variant	Exon 4 of 7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.993T>C	p.Phe331Phe	synonymous_variant	Exon 4 of 7	2		ENSP00000465408.1
NAGS	ENST00000592915.1	n.361T>C		non_coding_transcript_exon_variant	Exon 2 of 4	2

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

GnomAD3 exomes AF: 0.157 AC: 37897 AN: 241090 Hom.: 3476 AF XY: 0.158 AC XY: 20863 AN XY: 131760

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 SAS exome AF: 0.118

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

Gnomad4 AFR exome AF: 0.0922

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.171

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

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.0124

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.131

Alfa AF: 0.179 Hom.: 1418

Bravo AF: 0.146

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 28, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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PreventionGenetics, part of Exact Sciences

Significance: Likely 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

- -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperammonemia, type III Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

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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. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.72

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: rs55708447; hg19: chr17-42084067; COSMIC: COSV52814386; COSMIC: COSV52814386;