8-18400344-T-C

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.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 (★). 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 criteria provided, single submitter 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 -14 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]. Clinvar id is 723.Status of the report is criteria_provided_single_submitter, 1 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

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

NAT2-related disorder Benign:1

Benign, criteria provided, single submitter

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;