NM_000367.5:c.719A>C

Variant names:

• chr6-18130687-T-G
• rs1142345
• NM_000367.5:c.719A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_000367.5(TPMT):​c.719A>C​(p.Tyr240Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y240C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69

Genes affected

TPMT (HGNC:12014): (thiopurine S-methyltransferase) This gene encodes the enzyme that metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals, causing thiopurine S-methyltransferase deficiency. Related pseudogenes have been identified on chromosomes 3, 18 and X. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• BP6: Variant 6-18130687-T-G is Benign according to our data. Variant chr6-18130687-T-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.719A>C	p.Tyr240Ser	missense_variant	Exon 9 of 9	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.719A>C	p.Tyr240Ser	missense_variant	Exon 9 of 9	1	NM_000367.5	ENSP00000312304.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.71
Sift	Benign	0.033	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.79		Gain of disorder (P = 0.0123);
MVP		0.92
MPC		0.72
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.88

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: rs1142345; hg19: chr6-18130918;