8-18400593-G-T

Variant names:

• chr8-18400593-G-T
• rs1799930
• NM_000015.3:c.590G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000015.3(NAT2):​c.590G>T​(p.Arg197Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R197Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT2	NM_000015.3	c.590G>T	p.Arg197Leu	missense_variant	Exon 2 of 2	ENST00000286479.4	NP_000006.2
NAT2	XM_017012938.2	c.590G>T	p.Arg197Leu	missense_variant	Exon 3 of 3		XP_016868427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4	c.590G>T	p.Arg197Leu	missense_variant	Exon 2 of 2	1	NM_000015.3	ENSP00000286479.3
NAT2	ENST00000520116.1	c.200G>T	p.Arg67Leu	missense_variant	Exon 2 of 2	3		ENSP00000428416.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460956 Hom.: 0 Cov.: 48 AF XY: 0.00000138 AC XY: 1 AN XY: 726726

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 85928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.0	.;.
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.017	D;D
Vest4		0.65
ClinPred		0.91	D
GERP RS		2.5
gMVP		0.76
Mutation Taster		=42/58	disease causing

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: rs1799930; hg19: chr8-18258103;