8-18222324-G-C

Position:

• chr8-18222324-G-C

Variant summary

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

The NM_000662.8(NAT1):​c.277G>C​(p.Val93Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAT1 NM_000662.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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]

NAT1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAT1	NM_000662.8	c.277G>C	p.Val93Leu	missense_variant	3/3	ENST00000307719.9	NP_000653.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAT1	ENST00000307719.9	c.277G>C	p.Val93Leu	missense_variant	3/3	1	NM_000662.8	ENSP00000307218.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Oct 08, 2024

The c.277G>C (p.V93L) alteration is located in exon 3 (coding exon 1) of the NAT1 gene. This alteration results from a G to C substitution at nucleotide position 277, causing the valine (V) at amino acid position 93 to be replaced by a leucine (L). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.0066	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;T;T;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.0064
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.86	.;D;.;.;D;.
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H;H;H;H;.;H
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	N;N;N;N;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.013	D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D
Polyphen		0.68	P;P;P;P;P;P
Vest4		0.40
MutPred		0.74		.;.;.;.;Loss of sheet (P = 0.1501);.;
MVP		0.22
MPC		0.030
ClinPred		0.94	D
GERP RS		3.5
Varity_R		0.52
gMVP		0.83

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: rs1003496685; hg19: chr8-18079833;