rs4986997

Positions:

• chr8-18400414-A-C
• chr8-18400414-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_000015.3(NAT2):​c.411A>C​(p.Leu137Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 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 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.928

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAT2	NM_000015.3	c.411A>C	p.Leu137Phe	missense_variant	2/2	ENST00000286479.4
NAT2	XM_017012938.2	c.411A>C	p.Leu137Phe	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAT2	ENST00000286479.4	c.411A>C	p.Leu137Phe	missense_variant	2/2	1	NM_000015.3	P1
NAT2	ENST00000520116.1	c.21A>C	p.Leu7Phe	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151964 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248606 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459986 Hom.: 0 Cov.: 58 AF XY: 0.00000551 AC XY: 4 AN XY: 726262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151964 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74210

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.061	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0054	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.083	T;D
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.73		Gain of methylation at K141 (P = 0.1086);.;
MVP		0.46
MPC		0.020
ClinPred		0.98	D
GERP RS		0.46
gMVP		0.62

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: rs4986997; hg19: chr8-18257924;