8-18400194-G-A

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.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 (★). 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 criteria provided, single submitter 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 -14 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]. Clinvar id is 726.Status of the report is criteria_provided_single_submitter, 1 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

Submissions summary: Benign:1 Other: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

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;