rs4986783

Positions:

• chr8-18222687-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000662.8(NAT1):​c.640T>G​(p.Ser214Ala) 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 1,613,962 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032370389).
• 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.640T>G	p.Ser214Ala	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.640T>G	p.Ser214Ala	missense_variant	3/3	1	NM_000662.8	ENSP00000307218	P1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2749 AN: 152166 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00655

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0203 AC: 5085 AN: 250998 Hom.: 80 AF XY: 0.0216 AC XY: 2934 AN XY: 135652

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.00789

Gnomad SAS exome AF: 0.0274

Gnomad FIN exome AF: 0.00865

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0218 AC: 31883 AN: 1461680 Hom.: 434 Cov.: 32 AF XY: 0.0224 AC XY: 16275 AN XY: 727142

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.00587

Gnomad4 SAS exome AF: 0.0269

Gnomad4 FIN exome AF: 0.00957

Gnomad4 NFE exome AF: 0.0224

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0181 AC: 2757 AN: 152282 Hom.: 49 Cov.: 32 AF XY: 0.0174 AC XY: 1296 AN XY: 74458

Gnomad4 AFR AF: 0.00484

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00657

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.00876

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0251 Hom.: 96

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: 2539

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.20
DEOGEN2	Benign	0.049	T;T;T;T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00060	N
LIST_S2	Benign	0.0060	.;T;.;.;T;.
MetaRNN	Benign	0.0032	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.78	N;N;N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.54	T;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.069
MPC		0.015
ClinPred		0.00078	T
GERP RS		-5.9
Varity_R		0.20
gMVP		0.23

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: rs4986783; hg19: chr8-18080196; COSMIC: COSV56985645; COSMIC: COSV56985645;