rs1800462
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000367.5(TPMT):āc.238G>Cā(p.Ala80Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,984 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).
Frequency
Genomes: š 0.0020 ( 0 hom., cov: 32)
Exomes š: 0.0021 ( 9 hom. )
Consequence
TPMT
NM_000367.5 missense
NM_000367.5 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 2.18
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 Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.124863535).
BS2
?
High Homozygotes in GnomAdExome4 at 9 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPMT | NM_000367.5 | c.238G>C | p.Ala80Pro | missense_variant | 4/9 | ENST00000309983.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPMT | ENST00000309983.5 | c.238G>C | p.Ala80Pro | missense_variant | 4/9 | 1 | NM_000367.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00203 AC: 309AN: 152136Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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309
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32
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GnomAD3 exomes AF: 0.00174 AC: 437AN: 251094Hom.: 0 AF XY: 0.00188 AC XY: 256AN XY: 135822
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GnomAD4 exome AF: 0.00215 AC: 3142AN: 1461730Hom.: 9 Cov.: 32 AF XY: 0.00208 AC XY: 1510AN XY: 727156
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GnomAD4 genome ? AF: 0.00203 AC: 309AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.00223 AC XY: 166AN XY: 74438
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ExAC
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166
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ClinVar
Significance: drug response
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Thiopurine S-methyltransferase deficiency Other:1
drug response, no assertion criteria provided | literature only | OMIM | Feb 01, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at