rs1208

Positions:

• chr8-18400806-G-A
• chr8-18400806-G-C
• chr8-18400806-G-T

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.803G>A​(p.Arg268Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,610,782 control chromosomes in the GnomAD database, including 286,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.60 (28055 hom., cov: 31)
  • Exomes 𝑓: 0.59 (258400 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0830

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=6.8380643E-7).
• BP6: Variant 8-18400806-G-A is Benign according to our data. Variant chr8-18400806-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3059207.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAT2	NM_000015.3	c.803G>A	p.Arg268Lys	missense_variant	2/2	ENST00000286479.4
NAT2	XM_017012938.2	c.803G>A	p.Arg268Lys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAT2	ENST00000286479.4	c.803G>A	p.Arg268Lys	missense_variant	2/2	1	NM_000015.3	P1
NAT2	ENST00000520116.1	c.413G>A	p.Arg138Lys	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91371 AN: 151750 Hom.: 28047 Cov.: 31

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.960

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.594

GnomAD3 exomes AF: 0.619 AC: 153259 AN: 247584 Hom.: 48818 AF XY: 0.617 AC XY: 82695 AN XY: 134048

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.657

Gnomad ASJ exome AF: 0.558

Gnomad EAS exome AF: 0.959

Gnomad SAS exome AF: 0.645

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.591 AC: 862387 AN: 1458914 Hom.: 258400 Cov.: 39 AF XY: 0.592 AC XY: 429292 AN XY: 725744

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.655

Gnomad4 ASJ exome AF: 0.565

Gnomad4 EAS exome AF: 0.965

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.573

Gnomad4 OTH exome AF: 0.600

GnomAD4 genome AF: 0.602 AC: 91412 AN: 151868 Hom.: 28055 Cov.: 31 AF XY: 0.604 AC XY: 44838 AN XY: 74208

Gnomad4 AFR AF: 0.600

Gnomad4 AMR AF: 0.635

Gnomad4 ASJ AF: 0.559

Gnomad4 EAS AF: 0.960

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.598

Alfa AF: 0.575 Hom.: 41260

Bravo AF: 0.607

TwinsUK AF: 0.572 AC: 2120

ALSPAC AF: 0.581 AC: 2238

ESP6500AA AF: 0.601 AC: 2646

ESP6500EA AF: 0.576 AC: 4951

ExAC AF: 0.615 AC: 74582

Asia WGS AF: 0.779 AC: 2709 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.572

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NAT2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.24
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.035	T;T
MetaRNN	Benign	6.8e-7	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.041
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.013
MPC		0.0046
ClinPred		0.000022	T
GERP RS		1.5
gMVP		0.47

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: rs1208; hg19: chr8-18258316; COSMIC: COSV54061405;