8-18222492-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000662.8(NAT1):c.445G>A(p.Val149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,078 control chromosomes in the GnomAD database, including 483 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 49 hom., cov: 32)

Exomes 𝑓: 0.022 ( 434 hom. )

Consequence

NAT1
NM_000662.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 1.39

Publications

67 publications found

Variant links:

Genes affected

NAT1 (HGNC:7645): (N-acetyltransferase 1) This gene is one of two arylamine N-acetyltransferase (NAT) genes in the human genome, and is orthologous to the mouse and rat Nat2 genes. The enzyme encoded by this gene catalyzes the transfer of an acetyl group from acetyl-CoA to various arylamine and hydrazine substrates. This enzyme helps metabolize drugs and other xenobiotics, and functions in folate catabolism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

NAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013121098).

BP6

Variant 8-18222492-G-A is Benign according to our data. Variant chr8-18222492-G-A is described in ClinVar as Benign. ClinVar VariationId is 17808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000662.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NAT1	NM_000662.8	MANE Select	c.445G>A	p.Val149Ile	missense	Exon 3 of 3	NP_000653.3
NAT1	NM_001160175.4		c.631G>A	p.Val211Ile	missense	Exon 5 of 5	NP_001153647.1
NAT1	NM_001160176.4		c.631G>A	p.Val211Ile	missense	Exon 4 of 4	NP_001153648.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NAT1	ENST00000307719.9	TSL:1 MANE Select	c.445G>A	p.Val149Ile	missense	Exon 3 of 3	ENSP00000307218.4
NAT1	ENST00000518029.5	TSL:1	c.445G>A	p.Val149Ile	missense	Exon 4 of 4	ENSP00000428270.1
NAT1	ENST00000545197.3	TSL:5	c.631G>A	p.Val211Ile	missense	Exon 4 of 4	ENSP00000443194.1

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2751

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00495

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.00636

Gnomad SAS

AF:

0.0357

Gnomad FIN

AF:

0.00886

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0203

AC:

5103

AN:

251186

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0427

Gnomad EAS exome

AF:

0.00778

Gnomad FIN exome

AF:

0.00864

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0289

GnomAD4 exome

AF:

0.0218

AC:

31878

AN:

1461838

Hom.:

434

Cov.:

AF XY:

0.0224

AC XY:

16269

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00502

AC:

168

AN:

33472

American (AMR)

AF:

0.0115

AC:

512

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0446

AC:

1165

AN:

26134

East Asian (EAS)

AF:

0.00582

AC:

231

AN:

39700

South Asian (SAS)

AF:

0.0270

AC:

2328

AN:

86258

European-Finnish (FIN)

AF:

0.00957

AC:

511

AN:

53420

Middle Eastern (MID)

AF:

0.0801

AC:

462

AN:

5768

European-Non Finnish (NFE)

AF:

0.0224

AC:

24875

AN:

1111978

Other (OTH)

AF:

0.0269

AC:

1626

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1826

3652

5478

7304

9130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

852

1704

2556

3408

4260

<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:

0.0181

AC:

2759

AN:

152240

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1293

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00498

AC:

207

AN:

41546

American (AMR)

AF:

0.0147

AC:

225

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

146

AN:

3470

East Asian (EAS)

AF:

0.00637

AC:

AN:

5180

South Asian (SAS)

AF:

0.0363

AC:

175

AN:

4816

European-Finnish (FIN)

AF:

0.00886

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0255

AC:

1731

AN:

68008

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

139

277

416

554

693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0237

Hom.:

185

Bravo

AF:

0.0174

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0240

AC:

206

ExAC

AF:

0.0209

AC:

2536

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

NAT1*17 ALLELE

Other:1

Apr 20, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.78

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.028

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.51

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.6

PhyloP100

1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

0.12

REVEL

Benign

0.024

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.021

MPC

0.015

ClinPred

0.00042

GERP RS

0.34

Varity_R

0.035

gMVP

0.30

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over