chr8-18400262-A-G

Position:

• chr8-18400262-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000015.3(NAT2):​c.259A>G​(p.Thr87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13246101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAT2	NM_000015.3	c.259A>G	p.Thr87Ala	missense_variant	2/2	ENST00000286479.4	NP_000006.2
NAT2	XM_017012938.2	c.259A>G	p.Thr87Ala	missense_variant	3/3		XP_016868427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4	c.259A>G	p.Thr87Ala	missense_variant	2/2	1	NM_000015.3	ENSP00000286479.3
NAT2	ENST00000520116.1	c.-57-75A>G		intron_variant		3		ENSP00000428416.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.259A>G (p.T87A) alteration is located in exon 2 (coding exon 1) of the NAT2 gene. This alteration results from a A to G substitution at nucleotide position 259, causing the threonine (T) at amino acid position 87 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.95
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.077
Sift	Benign	0.065	T
Sift4G	Benign	0.15	T
Polyphen		0.059	B
Vest4		0.075
MutPred		0.64		Loss of glycosylation at T87 (P = 0.1913);
MVP		0.12
MPC		0.0053
ClinPred		0.78	D
GERP RS		1.7
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-18257772;