rs1799930

Positions:

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

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). 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 criteria provided, single submitter 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 -14 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]. Clinvar id is 722.Status of the report is criteria_provided_single_submitter, 1 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	UniProt
NAT2	NM_000015.3	c.590G>A	p.Arg197Gln	missense_variant	2/2	ENST00000286479.4
NAT2	XM_017012938.2	c.590G>A	p.Arg197Gln	missense_variant	3/3

Ensembl

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

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

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

NAT2-related disorder Benign:1

Benign, criteria provided, single submitter

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
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;