dbSNP rs1801280: NAT2:p.Ile114Asn (chr8-18400344-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000015.3(NAT2):c.341T>A(p.Ile114Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I114T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NAT2
NM_000015.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.86

Variant links:

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]

NAT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT2	NM_000015.3 link	c.341T>A	p.Ile114Asn	missense_variant	Exon 2 of 2	ENST00000286479.4	NP_000006.2	P11245A4Z6T7
NAT2	XM_017012938.2 link	c.341T>A	p.Ile114Asn	missense_variant	Exon 3 of 3		XP_016868427.1	P11245A4Z6T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAT2	ENST00000286479.4 link	c.341T>A	p.Ile114Asn	missense_variant	Exon 2 of 2	1	NM_000015.3	ENSP00000286479.3	P11245
NAT2	ENST00000520116 link	c.-50T>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 2	3		ENSP00000428416.1	E7EWF9
NAT2	ENST00000520116 link	c.-50T>A		5_prime_UTR_variant	Exon 2 of 2	3		ENSP00000428416.1	E7EWF9

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151644

Hom.:

Cov.:

show subpopulations

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461042

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726794

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33432

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44622

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26042

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39692

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86152

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53382

Gnomad4 NFE exome

AF:

9.00e-7

AC:

AN:

1111604

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60356

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151644

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74014

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.000014718

AN:

0.000014718

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

45713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

0.12

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0056

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-6.2

REVEL

Benign

0.091

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.76

MutPred

0.81

Loss of stability (P = 0.0289);

MVP

0.37

MPC

0.015

ClinPred

1.0

GERP RS

0.54

gMVP

0.81

Mutation Taster

=74/26

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over