chr17-44007720-G-T

Variant names:

• chr17-44007720-G-T
• rs369492320
• NM_153006.3:c.1398G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_153006.3(NAGS):​c.1398G>T​(p.Arg466Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000069 in 1,449,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R466R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NAGS NM_153006.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.93
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-44007720-G-T is Benign according to our data. Variant chr17-44007720-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1613751.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGS	NM_153006.3	c.1398G>T	p.Arg466Arg	synonymous_variant	Exon 6 of 7	ENST00000293404.8	NP_694551.1
NAGS	XM_011524439.2	c.900G>T	p.Arg300Arg	synonymous_variant	Exon 6 of 7		XP_011522741.1
NAGS	XM_011524438.2	c.1268+226G>T		intron_variant	Intron 5 of 5		XP_011522740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGS	ENST00000293404.8	c.1398G>T	p.Arg466Arg	synonymous_variant	Exon 6 of 7	1	NM_153006.3	ENSP00000293404.2
NAGS	ENST00000589767.1	c.1329G>T	p.Arg443Arg	synonymous_variant	Exon 6 of 7	2		ENSP00000465408.1
NAGS	ENST00000592915.1	n.1286G>T		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449432 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719844

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33182

American (AMR) AF: 0.00 AC: 0 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39076

South Asian (SAS) AF: 0.00 AC: 0 AN: 84110

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105544

Other (OTH) AF: 0.00 AC: 0 AN: 59858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperammonemia, type III Benign:1

Oct 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		3.9

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: rs369492320; hg19: chr17-42085088;