TPMT

thiopurine S-methyltransferase, the group of 7BS small molecule methyltransferases

Basic information

Region (hg38): 6:18128311-18155077

Links

ENSG00000137364

∙ NCBI:7172 ∙ OMIM:187680 ∙ HGNC:12014 ∙ Uniprot:P51580 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thiopurine S-methyltransferase deficiency	AR	Pharmacogenomic	Dose adjustment/selection of specific medications (eg, azathioprine, cisplatin, mercaptopurine, s-adenoslymethionine, thioguanine) may be indicated in order to avoid severe toxicity	Biochemical	2758725; 1960624; 7862671; 8644731; 9177237; 11304783; 15228163; 16220112; 19898482

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TPMT gene.

not_specified (16 variants)
Thiopurine_S-methyltransferase_deficiency (6 variants)
Thiopurine_response (4 variants)
not_provided (3 variants)
TPMT-related_disorder (2 variants)
Azathioprine_response (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TPMT gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000367.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	3 clinvar		4
missense			22 clinvar	1 clinvar		23
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	27	4	0

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TPMT	protein_coding	protein_coding	ENST00000309983	8	26764

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000711	0.740	125645	0	103	125748	0.000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.290	120	129	0.928	0.00000646	1618
Missense in Polyphen		27	31.177	0.86602		410
Synonymous	0.894	36	43.5	0.828	0.00000231	433
Loss of Function	1.15	10	14.8	0.678	6.24e-7	181

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000358	0.000358
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00120	0.00120
European (Non-Finnish)	0.000493	0.000492
Middle Eastern	0.000109	0.000109
South Asian	0.000327	0.000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6- TG) using S-adenosyl-L-methionine as the methyl donor (PubMed:657528, PubMed:18484748). TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified. {ECO:0000269|PubMed:18484748, ECO:0000269|PubMed:657528, ECO:0000305}.;
Pathway: Drug metabolism - other enzymes - Homo sapiens (human);Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Mercaptopurine Action Pathway;Azathioprine Action Pathway;Thioguanine Action Pathway;Mercaptopurine Metabolism Pathway;Metapathway biotransformation Phase I and II;Methylation Pathways;Methylation;Phase II - Conjugation of compounds;Biological oxidations;Metabolism (Consensus)

Recessive Scores

pRec: 0.166

Intolerance Scores

loftool: 0.703
rvis_EVS: 0.79
rvis_percentile_EVS: 87.4

Haploinsufficiency Scores

pHI: 0.0952
hipred: N
hipred_score: 0.170
ghis: 0.402

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.129

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

Gene name: Tpmt
Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype;

Gene ontology

Biological process: nucleobase-containing compound metabolic process;drug metabolic process;methylation
Cellular component: cytosol
Molecular function: thiopurine S-methyltransferase activity;S-adenosyl-L-methionine binding