TPMT

protein-coding

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

Gene summary

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]

MANE transcript

NM_000367.5

Inheritance

ClinVar variants

U:36B:4

Top phenotype

Thiopurine S-methyltransferase deficiency

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr6:18,128,311-18,155,077

External References & Databases

Ensembl (ENSG00000137364)

Transcript & Mutation Effects

hg38 • Region Span ~26.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Thiopurine S-methyltransferase deficiencyAR

Manifestation: Biochemical

Intervention: Pharmacogenomic

Rationale: Dose adjustment/selection of specific medications (eg, azathioprine, cisplatin, mercaptopurine, s-adenoslymethionine, thioguanine) may be indicated in order to avoid severe toxicity

Refs: 2758725; 1960624; 7862671; 8644731; 9177237; 11304783; 15228163; 16220112; 19898482

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPMT variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 22

Thiopurine responseTotal: 4

Thiopurine S-methyltransferase deficiencyTotal: 4

not providedTotal: 3

TPMT-related disorderTotal: 2

Azathioprine responseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000367.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	3 clinvar		4
missense			28 clinvar	1 clinvar		29
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	36	4	0	40

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000367.5	RefSeq	NP_000358.1	8	MANE Select
ENST00000309983.5	Ensembl	ENSP00000312304.4	8	MANE Select
NM_001346817.1	RefSeq	NP_001333746.1	8	Standard
NM_001346818.1	RefSeq	NP_001333747.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Drug metabolism - other enzymes - Homo sapiens (human)
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics
Mercaptopurine Action Pathway
Azathioprine Action Pathway
Thioguanine Action Pathway

Biological Process

nucleobase-containing compound metabolic process
drug metabolic process
methylation

Molecular Function

thiopurine S-methyltransferase activity
S-adenosyl-L-methionine binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000309983
Coding exons: 8
Length: 26764
Individuals with no LoFs: 125645
Homozygous LoFs: 0
Heterozygous LoFs: 103
Defined: 125748
p: 0.000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.290	120	129	0.928	0.00000646	1618
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.00049	0.00049	rare
South Asian	0.00033	0.00033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.166

Intolerance Scores

LoFtool: 0.703
RVIS EVS: 0.79
RVIS percentile EVS: 87.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.129

Gene Damage Prediction

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