NM_000015.3:c.590G>A

Variant names:

Variant summary

Our verdict is The variant received -11 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6

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 cumulative frequency of 0.288 (AC=464,073) in the gnomAD database across 1,612,574 control chromosomes, including 68,230 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.356. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.27 ( 5830 hom., cov: 31)

Exomes 𝑓: 0.29 ( 62400 hom. )

Consequence

NAT2
NM_000015.3 missense

Scores

Clinical Significance

Benign; drug response no assertion criteria provided B:1O:1

Conservation

PhyloP100: 1.09

Publications

449 publications found

Variant links:

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]

NAT2 Gene-Disease associations (from GenCC):

acetylation, slow
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

NAT2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000015.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -11 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3560 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000015.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT2	NM_000015.3	MANE Select	c.590G>A	p.Arg197Gln	missense	Exon 2 of 2	NP_000006.2	P11245

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NAT2	ENST00000286479.4	TSL:1 MANE Select	c.590G>A	p.Arg197Gln	missense	Exon 2 of 2	ENSP00000286479.3	P11245
NAT2	ENST00000893781.1		c.590G>A	p.Arg197Gln	missense	Exon 3 of 3	ENSP00000563840.1
NAT2	ENST00000893782.1		c.590G>A	p.Arg197Gln	missense	Exon 3 of 3	ENSP00000563841.1

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41457

AN:

151716

Hom.:

5835

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.273

AC:

68188

AN:

249910

AF XY:

0.282

show subpopulations

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 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.:

AF XY:

0.292

AC XY:

212083

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.257

AC:

8593

AN:

33408

American (AMR)

AF:

0.160

AC:

7136

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

9477

AN:

26070

East Asian (EAS)

AF:

0.222

AC:

8817

AN:

39696

South Asian (SAS)

AF:

0.359

AC:

30877

AN:

85914

European-Finnish (FIN)

AF:

0.240

AC:

12816

AN:

53316

Middle Eastern (MID)

AF:

0.286

AC:

1647

AN:

5754

European-Non Finnish (NFE)

AF:

0.293

AC:

325416

AN:

1111648

Other (OTH)

AF:

0.296

AC:

17844

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16416

32832

49248

65664

82080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10804

21608

32412

43216

54020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.273

AC:

41450

AN:

151834

Hom.:

5830

Cov.:

AF XY:

0.270

AC XY:

20060

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.258

AC:

10698

AN:

41392

American (AMR)

AF:

0.207

AC:

3153

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1253

AN:

3466

East Asian (EAS)

AF:

0.257

AC:

1323

AN:

5154

South Asian (SAS)

AF:

0.363

AC:

1749

AN:

4812

European-Finnish (FIN)

AF:

0.234

AC:

2458

AN:

10502

Middle Eastern (MID)

AF:

0.277

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.292

AC:

19841

AN:

67936

Other (OTH)

AF:

0.271

AC:

572

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1543

3087

4630

6174

7717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.282

Hom.:

30268

Bravo

AF:

0.264

Asia WGS

AF:

0.314

AC:

1091

AN:

3478

EpiCase

AF:

0.294

EpiControl

AF:

0.294

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.191

AC:

23489

AN:

122734

Turkish Variome

AF:

0.311

AC:

2086

AN:

6714

Hom.:

359

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.262

AC:

2349

AN:

8960

Hom.:

334

ABraOM SABE-WGS-1171

AF:

0.244

AC:

572

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign; drug response

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

NAT2-related disorder (1)

Slow acetylator due to N-acetyltransferase enzyme variant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0094

Eigen

Benign

0.088

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.83

MetaRNN

Benign

0.00046

MetaSVM

Benign

-0.94

PhyloP100

1.1

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.17

Sift

Benign

0.054

Sift4G

Benign

0.091

gMVP

0.69

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over