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GeneBe

rs1142345

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000367.5(TPMT):c.719A>T(p.Tyr240Phe) 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. 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. Y240C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TPMT
NM_000367.5 missense

Scores

1
9
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.69
Variant links:
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]

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ACMG classification

Classification made for transcript

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, 0.766

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TPMTNM_000367.5 linkuse as main transcriptc.719A>T p.Tyr240Phe missense_variant 9/9 ENST00000309983.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TPMTENST00000309983.5 linkuse as main transcriptc.719A>T p.Tyr240Phe missense_variant 9/91 NM_000367.5 P1

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
Benign
0.11
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Benign
-0.19
Cadd
Uncertain
24
Dann
Uncertain
0.98
DEOGEN2
Benign
0.24
T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.017
T
MetaRNN
Pathogenic
0.77
D
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.4
N
REVEL
Uncertain
0.35
Sift
Benign
0.13
T
Sift4G
Benign
0.12
T
Polyphen
0.95
P
Vest4
0.49
MutPred
0.85
Gain of methylation at K238 (P = 0.0633);
MVP
0.84
MPC
0.22
ClinPred
0.90
D
GERP RS
5.9
Varity_R
0.45
gMVP
0.66

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: chr6-18130918; API