TPMT

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

Basic information

Region (hg38): 6:18128310-18155077

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.

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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	4		5
missense			10	3		13
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding			3			3
Total	0	0	14	7	0

Variants in TPMT

This is a list of pathogenic ClinVar variants found in the TPMT region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-18128886-A-ATTTT		Thiopurine S-methyltransferase deficiency	Uncertain significance (Jun 14, 2016)
6-18129765-AGATT-A		Thiopurine S-methyltransferase deficiency	Uncertain significance (Jun 14, 2016)
6-18130254-C-T		Thiopurine S-methyltransferase deficiency	Uncertain significance (Jun 14, 2016)
6-18130687-T-C		Thiopurine S-methyltransferase deficiency	Likely benign; other (Jul 01, 2024)
6-18130702-A-G		not specified	Uncertain significance (Nov 22, 2021)
6-18130716-C-G		not specified	Uncertain significance (Mar 01, 2023)
6-18130758-A-T			not provided (-)
6-18130762-C-T		Thiopurine S-methyltransferase deficiency	drug response (Feb 01, 1999)
6-18130781-C-T		Thiopurine S-methyltransferase deficiency	drug response (May 15, 2019)
6-18133807-G-A		not specified	Uncertain significance (May 23, 2024)
6-18133860-C-T		not specified	Uncertain significance (Jul 13, 2021)
6-18133884-G-C		Thiopurine S-methyltransferase deficiency	drug response (Oct 01, 2007)
6-18133885-C-T		not specified	Uncertain significance (May 06, 2024)
6-18133887-T-C		Thiopurine response	drug response (Dec 01, 2014)
6-18138983-G-A		not specified	Likely benign (Apr 12, 2017)
6-18138997-C-T		Thiopurine S-methyltransferase deficiency • TPMT-related disorder	Benign/Likely benign; other (Jul 01, 2024)
6-18139041-C-T		Azathioprine response • TPMT-related disorder	Likely benign (Oct 22, 2019)
6-18139672-G-A		not specified	Likely benign (Dec 27, 2022)
6-18139694-C-T			Likely benign (Apr 01, 2023)
6-18139709-C-T		TPMT-related disorder	Likely benign (Dec 03, 2019)
6-18143627-A-T		Thiopurine S-methyltransferase deficiency	Uncertain significance (Jun 14, 2016)
6-18143653-C-T			Likely benign (May 01, 2022)
6-18143668-T-G		not specified	Uncertain significance (Dec 13, 2023)
6-18143700-C-T		Thiopurine response	drug response (Mar 01, 2015)
6-18143724-C-G		Thiopurine S-methyltransferase deficiency	drug response (Feb 01, 1999)

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