chr8-18400344-T-C

Position:

• chr8-18400344-T-C

Variant summary

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

The NM_000015.3(NAT2):​c.341T>C​(p.Ile114Thr) variant causes a missense change. The variant allele was found at a frequency of 0.421 in 1,612,532 control chromosomes in the GnomAD database, including 148,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,drug response (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (11840 hom., cov: 29)
  • Exomes 𝑓: 0.42 (136583 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Benign; drug response no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 3.86

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=0.0032346249).
• BP6: Variant 8-18400344-T-C is Benign according to our data. Variant chr8-18400344-T-C is described in ClinVar as [Benign, drug_response]. Clinvar id is 723.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAT2	NM_000015.3	c.341T>C	p.Ile114Thr	missense_variant	2/2	ENST00000286479.4
NAT2	XM_017012938.2	c.341T>C	p.Ile114Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAT2	ENST00000286479.4	c.341T>C	p.Ile114Thr	missense_variant	2/2	1	NM_000015.3	P1
NAT2	ENST00000520116.1	c.-50T>C		5_prime_UTR_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57850 AN: 151550 Hom.: 11834 Cov.: 29

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.395

GnomAD3 exomes AF: 0.381 AC: 95254 AN: 250338 Hom.: 19891 AF XY: 0.386 AC XY: 52267 AN XY: 135308

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.451

Gnomad EAS exome AF: 0.0384

Gnomad SAS exome AF: 0.346

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.425 AC: 620630 AN: 1460862 Hom.: 136583 Cov.: 55 AF XY: 0.424 AC XY: 308238 AN XY: 726712

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.443

Gnomad4 EAS exome AF: 0.0268

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.459

Gnomad4 NFE exome AF: 0.452

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.382 AC: 57876 AN: 151670 Hom.: 11840 Cov.: 29 AF XY: 0.379 AC XY: 28069 AN XY: 74090

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.0366

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.392

Alfa AF: 0.424 Hom.: 20369

Bravo AF: 0.370

TwinsUK AF: 0.448 AC: 1661

ALSPAC AF: 0.439 AC: 1691

ESP6500AA AF: 0.298 AC: 1311

ESP6500EA AF: 0.445 AC: 3831

ExAC AF: 0.384 AC: 46624

Asia WGS AF: 0.197 AC: 687 AN: 3478

EpiCase AF: 0.446

EpiControl AF: 0.445

ClinVar

Significance: Benign; drug response

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

NAT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

This variant is classified as 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	0.086
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.95	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.098
Sift	Benign	0.048	D
Sift4G	Uncertain	0.043	D
Polyphen		0.37	B
Vest4		0.12
MPC		0.010
ClinPred		0.064	T
GERP RS		0.54
gMVP		0.68

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: rs1801280; hg19: chr8-18257854; COSMIC: COSV54061433;