chr8-18400194-G-A

Position:

• chr8-18400194-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000015.3(NAT2):​c.191G>A​(p.Arg64Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00455 in 1,613,190 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R64W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (148 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (125 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Likely benign; drug response no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 4.28

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=0.0065536797).
• BP6: Variant 8-18400194-G-A is Benign according to our data. Variant chr8-18400194-G-A is described in ClinVar as [Likely_benign, drug_response]. Clinvar id is 726.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAT2	NM_000015.3	c.191G>A	p.Arg64Gln	missense_variant	2/2	ENST00000286479.4
NAT2	XM_017012938.2	c.191G>A	p.Arg64Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAT2	ENST00000286479.4	c.191G>A	p.Arg64Gln	missense_variant	2/2	1	NM_000015.3	P1
NAT2	ENST00000520116.1	c.-57-143G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3658 AN: 152072 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00620 AC: 1554 AN: 250678 Hom.: 53 AF XY: 0.00447 AC XY: 605 AN XY: 135480

Gnomad AFR exome AF: 0.0822

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00251 AC: 3673 AN: 1461002 Hom.: 125 Cov.: 30 AF XY: 0.00211 AC XY: 1535 AN XY: 726678

Gnomad4 AFR exome AF: 0.0856

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.00557

GnomAD4 genome AF: 0.0241 AC: 3669 AN: 152188 Hom.: 148 Cov.: 32 AF XY: 0.0237 AC XY: 1766 AN XY: 74406

Gnomad4 AFR AF: 0.0826

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00640 Hom.: 41

Bravo AF: 0.0273

ESP6500AA AF: 0.0772 AC: 340

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00787 AC: 955

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign; drug response

Submissions summary: Benign:1 Other: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

Jan 13, 2020

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). -

Slow acetylator due to N-acetyltransferase enzyme variant Other:1

drug response, no assertion criteria provided

literature only

OMIM

Oct 28, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	0.059
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.98	D;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.28
MVP		0.29
MPC		0.019
ClinPred		0.066	T
GERP RS		1.1
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801279; hg19: chr8-18257704;