rs1799930

Positions:

• chr8-18400593-G-A
• chr8-18400593-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000015.3(NAT2):​c.590G>A​(p.Arg197Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,612,574 control chromosomes in the GnomAD database, including 68,230 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,drug response (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (5830 hom., cov: 31)
  • Exomes 𝑓: 0.29 (62400 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Benign; drug response no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 1.09

Genes affected

NAT2 (HGNC:7646): (N-acetyltransferase 2) This gene encodes an enzyme that functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with higher incidences of cancer and drug toxicity. A second polymorphic arylamine N-acetyltransferase gene (NAT1), is located near this gene (NAT2). [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.61936E-4).
• BP6: Variant 8-18400593-G-A is Benign according to our data. Variant chr8-18400593-G-A is described in ClinVar as [Benign, drug_response]. Clinvar id is 722.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAT2	NM_000015.3	c.590G>A	p.Arg197Gln	missense_variant	2/2	ENST00000286479.4	NP_000006.2
NAT2	XM_017012938.2	c.590G>A	p.Arg197Gln	missense_variant	3/3		XP_016868427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4	c.590G>A	p.Arg197Gln	missense_variant	2/2	1	NM_000015.3	ENSP00000286479	P1
NAT2	ENST00000520116.1	c.200G>A	p.Arg67Gln	missense_variant	2/2	3		ENSP00000428416

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41457 AN: 151716 Hom.: 5835 Cov.: 31

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.274

GnomAD3 exomes AF: 0.273 AC: 68188 AN: 249910 Hom.: 9856 AF XY: 0.282 AC XY: 38067 AN XY: 135124

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.258

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.289 AC: 422623 AN: 1460740 Hom.: 62400 Cov.: 48 AF XY: 0.292 AC XY: 212083 AN XY: 726624

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.240

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.273 AC: 41450 AN: 151834 Hom.: 5830 Cov.: 31 AF XY: 0.270 AC XY: 20060 AN XY: 74176

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.363

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.271

Alfa AF: 0.283 Hom.: 15609

Bravo AF: 0.264

TwinsUK AF: 0.290 AC: 1076

ALSPAC AF: 0.303 AC: 1168

ESP6500AA AF: 0.266 AC: 1171

ESP6500EA AF: 0.290 AC: 2497

ExAC AF: 0.277 AC: 33610

Asia WGS AF: 0.314 AC: 1091 AN: 3478

EpiCase AF: 0.294

EpiControl AF: 0.294

ClinVar

Significance: Benign; drug response

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

NAT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Slow acetylator due to N-acetyltransferase enzyme variant Other:1

drug response, no assertion criteria provided

literature only

OMIM

Oct 28, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0094	.;T
Eigen	Benign	0.088
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.00046	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.0016	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.17
Sift	Benign	0.054	T;T
Sift4G	Benign	0.091	T;D
Polyphen		1.0	D;.
Vest4		0.082
MPC		0.0095
ClinPred		0.042	T
GERP RS		2.5
gMVP		0.69

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: rs1799930; hg19: chr8-18258103; COSMIC: COSV54061522;