rs1208

Positions:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
NAT2	NM_000015.3	c.803G>A	p.Arg268Lys	missense_variant	2/2	ENST00000286479.4	NP_000006.2
NAT2	XM_017012938.2	c.803G>A	p.Arg268Lys	missense_variant	3/3		XP_016868427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4	c.803G>A	p.Arg268Lys	missense_variant	2/2	1	NM_000015.3	ENSP00000286479	P1
NAT2	ENST00000520116.1	c.413G>A	p.Arg138Lys	missense_variant	2/2	3		ENSP00000428416

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: no assertion criteria provided

Submissions by phenotype

NAT2-related disorder Benign:1

Likely benign, no assertion criteria provided

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
DEOGEN2	Benign	0.0040	.;T
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;