Genetic Variant NM_000015.3:c.857G>A (chr8-18400860-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000015.3(NAT2):c.857G>A(p.Gly286Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,592,210 control chromosomes in the GnomAD database, including 1,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.041 ( 228 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1463 hom. )

Consequence

NAT2
NM_000015.3 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -1.92

Publications

378 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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016905367).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT2	NM_000015.3 link	c.857G>A	p.Gly286Glu	missense_variant	Exon 2 of 2	ENST00000286479.4	NP_000006.2
NAT2	XM_017012938.2 link	c.857G>A	p.Gly286Glu	missense_variant	Exon 3 of 3		XP_016868427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4 link	c.857G>A	p.Gly286Glu	missense_variant	Exon 2 of 2	1	NM_000015.3	ENSP00000286479.3
NAT2	ENST00000520116.1 link	c.467G>A	p.Gly156Glu	missense_variant	Exon 2 of 2	3		ENSP00000428416.1

Frequencies

GnomAD3 genomes

AF:

0.0413

AC:

6284

AN:

152096

Hom.:

227

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0331

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0958

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.0739

Gnomad FIN

AF:

0.0340

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0545

GnomAD2 exomes

AF:

0.0576

AC:

13017

AN:

226094

AF XY:

0.0539

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.142

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.0367

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0510

GnomAD4 exome

AF:

0.0338

AC:

48617

AN:

1439998

Hom.:

1463

Cov.:

AF XY:

0.0341

AC XY:

24432

AN XY:

715712

show subpopulations

African (AFR)

AF:

0.0293

AC:

944

AN:

32224

American (AMR)

AF:

0.137

AC:

5553

AN:

40414

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

440

AN:

24566

East Asian (EAS)

AF:

0.126

AC:

5001

AN:

39600

South Asian (SAS)

AF:

0.0690

AC:

5653

AN:

81894

European-Finnish (FIN)

AF:

0.0370

AC:

1929

AN:

52084

Middle Eastern (MID)

AF:

0.0463

AC:

260

AN:

5610

European-Non Finnish (NFE)

AF:

0.0239

AC:

26411

AN:

1104226

Other (OTH)

AF:

0.0409

AC:

2426

AN:

59380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2012

4023

6035

8046

10058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1170

2340

3510

4680

5850

<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:

0.0414

AC:

6297

AN:

152212

Hom.:

228

Cov.:

AF XY:

0.0446

AC XY:

3319

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0330

AC:

1372

AN:

41542

American (AMR)

AF:

0.0962

AC:

1470

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3468

East Asian (EAS)

AF:

0.151

AC:

779

AN:

5164

South Asian (SAS)

AF:

0.0740

AC:

356

AN:

4814

European-Finnish (FIN)

AF:

0.0340

AC:

360

AN:

10602

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0257

AC:

1751

AN:

68018

Other (OTH)

AF:

0.0573

AC:

121

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

299

599

898

1198

1497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0326

Hom.:

601

Bravo

AF:

0.0470

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.0288

AC:

126

ESP6500EA

AF:

0.0199

AC:

170

ExAC

AF:

0.0520

AC:

6297

Asia WGS

AF:

0.106

AC:

367

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Slow acetylator due to N-acetyltransferase enzyme variant

Other:1

Oct 28, 2012

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.0020

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.036

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

.;.

PhyloP100

-1.9

PrimateAI

Benign

0.23

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.022

Sift

Benign

0.48

T;T

Sift4G

Benign

0.97

T;T

Vest4

0.11

ClinPred

0.0054

GERP RS

-5.1

gMVP

0.65

Mutation Taster

=97/3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over