Genetic Variant NAT1:p.Arg64Trp (chr8-18222237-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000662.8(NAT1):c.190C>T(p.Arg64Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,614,042 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 33 hom. )

Consequence

NAT1
NM_000662.8 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.833

Publications

49 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021713734).

BP6

Variant 8-18222237-C-T is Benign according to our data. Variant chr8-18222237-C-T is described in ClinVar as Benign. ClinVar VariationId is 252546.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 547 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT1	NM_000662.8 link	c.190C>T	p.Arg64Trp	missense_variant	Exon 3 of 3	ENST00000307719.9	NP_000653.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT1	ENST00000307719.9 link	c.190C>T	p.Arg64Trp	missense_variant	Exon 3 of 3	1	NM_000662.8	ENSP00000307218.4

Frequencies

GnomAD3 genomes

AF:

0.00360

AC:

547

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00685

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00335

AC:

841

AN:

251168

AF XY:

0.00347

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00596

AC:

8714

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

4148

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

33472

American (AMR)

AF:

0.00132

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000359

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00213

AC:

114

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00737

AC:

8192

AN:

1111980

Other (OTH)

AF:

0.00454

AC:

274

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

519

1038

1558

2077

2596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.00359

AC:

547

AN:

152214

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41534

American (AMR)

AF:

0.000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00685

AC:

466

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00526

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00312

AC:

379

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T;T;.;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

-0.026

FATHMM_MKL

Benign

0.28

LIST_S2

Pathogenic

0.99

.;D;.;.;D;.

M_CAP

Benign

0.0085

MetaRNN

Benign

0.022

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

4.1

H;H;H;H;.;H

PhyloP100

0.83

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-7.9

D;D;D;D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.68

MVP

0.53

MPC

0.12

ClinPred

0.10

GERP RS

1.2

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.92

gMVP

0.94

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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