rs4987076

Positions:

• chr8-18222492-G-A
• chr8-18222492-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000662.8(NAT1):​c.445G>A​(p.Val149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,078 control chromosomes in the GnomAD database, including 483 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.018 (49 hom., cov: 32)
  • Exomes 𝑓: 0.022 (434 hom.)
• Consequence: NAT1 NM_000662.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.39

Genes affected

NAT1 (HGNC:7645): (N-acetyltransferase 1) This gene is one of two arylamine N-acetyltransferase (NAT) genes in the human genome, and is orthologous to the mouse and rat Nat2 genes. The enzyme encoded by this gene catalyzes the transfer of an acetyl group from acetyl-CoA to various arylamine and hydrazine substrates. This enzyme helps metabolize drugs and other xenobiotics, and functions in folate catabolism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013121098).
• BP6: Variant 8-18222492-G-A is Benign according to our data. Variant chr8-18222492-G-A is described in ClinVar as [Benign]. Clinvar id is 17808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18222492-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAT1	NM_000662.8	c.445G>A	p.Val149Ile	missense_variant	3/3	ENST00000307719.9	NP_000653.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAT1	ENST00000307719.9	c.445G>A	p.Val149Ile	missense_variant	3/3	1	NM_000662.8	ENSP00000307218	P1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2751 AN: 152122 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.00886

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0203 AC: 5103 AN: 251186 Hom.: 80 AF XY: 0.0217 AC XY: 2941 AN XY: 135736

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0427

Gnomad EAS exome AF: 0.00778

Gnomad SAS exome AF: 0.0276

Gnomad FIN exome AF: 0.00864

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0218 AC: 31878 AN: 1461838 Hom.: 434 Cov.: 32 AF XY: 0.0224 AC XY: 16269 AN XY: 727232

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0446

Gnomad4 EAS exome AF: 0.00582

Gnomad4 SAS exome AF: 0.0270

Gnomad4 FIN exome AF: 0.00957

Gnomad4 NFE exome AF: 0.0224

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0181 AC: 2759 AN: 152240 Hom.: 49 Cov.: 32 AF XY: 0.0174 AC XY: 1293 AN XY: 74424

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.00886

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0240 Hom.: 109

Bravo AF: 0.0174

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0240 AC: 206

ExAC AF: 0.0209 AC: 2536

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

NAT1*17 ALLELE Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.78
DANN	Benign	0.17
DEOGEN2	Benign	0.028	T;T;T;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.51	.;T;.;.;T;.
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.6	N;N;N;N;.;N
MutationTaster	Benign	4.5e-12	A;A;A;A;A;A;A;A
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.12	N;N;N;N;N;N
REVEL	Benign	0.024
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.021
MPC		0.015
ClinPred		0.00042	T
GERP RS		0.34
Varity_R		0.035
gMVP		0.30

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: rs4987076; hg19: chr8-18080001; COSMIC: COSV56984779; COSMIC: COSV56984779;