8-18222687-T-G

Variant names:

• chr8-18222687-T-G
• rs4986783
• NM_000662.8:c.640T>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 43 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000662.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT1	NM_000662.8	MANE Select	c.640T>G	p.Ser214Ala	missense	Exon 3 of 3	NP_000653.3
	NAT1	NM_001160175.4		c.826T>G	p.Ser276Ala	missense	Exon 5 of 5	NP_001153647.1
	NAT1	NM_001160176.4		c.826T>G	p.Ser276Ala	missense	Exon 4 of 4	NP_001153648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT1	ENST00000307719.9	TSL:1 MANE Select	c.640T>G	p.Ser214Ala	missense	Exon 3 of 3	ENSP00000307218.4
	NAT1	ENST00000518029.5	TSL:1	c.640T>G	p.Ser214Ala	missense	Exon 4 of 4	ENSP00000428270.1
	NAT1	ENST00000545197.3	TSL:5	c.826T>G	p.Ser276Ala	missense	Exon 4 of 4	ENSP00000443194.1

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

GnomAD2 exomes AF: 0.0203 AC: 5085 AN: 250998 AF XY: 0.0216

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 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

African (AFR) AF: 0.00502 AC: 168 AN: 33468

American (AMR) AF: 0.0114 AC: 510 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1159 AN: 26112

East Asian (EAS) AF: 0.00587 AC: 233 AN: 39698

South Asian (SAS) AF: 0.0269 AC: 2320 AN: 86214

European-Finnish (FIN) AF: 0.00957 AC: 511 AN: 53406

Middle Eastern (MID) AF: 0.0801 AC: 462 AN: 5768

European-Non Finnish (NFE) AF: 0.0224 AC: 24888 AN: 1111932

Other (OTH) AF: 0.0270 AC: 1632 AN: 60386

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

African (AFR) AF: 0.00484 AC: 201 AN: 41556

American (AMR) AF: 0.0146 AC: 224 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3468

East Asian (EAS) AF: 0.00657 AC: 34 AN: 5176

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4822

European-Finnish (FIN) AF: 0.00876 AC: 93 AN: 10618

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1736 AN: 68022

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0232 Hom.: 120

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 v4.9

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
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00060	N
LIST_S2	Benign	0.0060	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.78	N
PhyloP100		-0.075
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.023
Sift	Benign	0.54	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.069
MPC		0.015
ClinPred		0.00078	T
GERP RS		-5.9
Varity_R		0.20
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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