TPK1

thiamin pyrophosphokinase 1

Basic information

Region (hg38): 7:144451941-144836395

Links

ENSG00000196511 ∙ NCBI:27010 ∙ OMIM:606370 ∙ HGNC:17358 ∙ Uniprot:Q9H3S4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Strong), mode of inheritance: AR
• childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Supportive), mode of inheritance: AR
• childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Strong), mode of inheritance: AR
• Leigh syndrome (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thiamine metabolism dysfunction syndrome 5	AR	Biochemical	In some individuals, thiamine supplementation appears to have beneficial effect (related compounds may be beneficial as well)	Biochemical; Neurologic	22152682

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TPK1 gene.

• Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (8 variants)
• not provided (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TPK1 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	47		48
missense	1	5	92	1		99
nonsense	1	1				2
start loss						0
frameshift	4	2				6
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	4				6
splice region	1		6	10	2	19
non coding			1	47	25	73
Total	8	12	96	95	25

Highest pathogenic variant AF is 0.000105

Variants in TPK1

This is a list of pathogenic ClinVar variants found in the TPK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-144453562-T-C		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Apr 25, 2022)
7-144453571-G-C		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Oct 12, 2021)
7-144453573-A-G		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Feb 26, 2020)
7-144453576-G-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Oct 05, 2022)
7-144453577-G-A		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Dec 19, 2019)
7-144453590-C-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Aug 23, 2022)
7-144453600-A-T		Inborn genetic diseases • Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Feb 05, 2024)
7-144453601-C-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Aug 09, 2022)
7-144453605-A-G			Likely benign (Oct 25, 2017)
7-144453608-C-G		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Sep 06, 2022)
7-144453608-C-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Apr 20, 2023)
7-144453610-C-A			Uncertain significance (Nov 19, 2021)
7-144453610-C-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Oct 24, 2022)
7-144453609-C-CCGT		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Mar 27, 2020)
7-144453611-G-A		not specified • Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Oct 23, 2023)
7-144453613-C-G		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Pathogenic/Likely pathogenic (May 11, 2023)
7-144453613-C-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Jan 19, 2024)
7-144453614-G-A		not specified • Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Benign/Likely benign (Feb 01, 2024)
7-144453615-T-C		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Uncertain significance (Mar 06, 2020)
7-144453619-T-C			Uncertain significance (Dec 03, 2023)
7-144453620-A-G		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Feb 11, 2022)
7-144453621-T-C		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency • Inborn genetic diseases	Conflicting classifications of pathogenicity (May 16, 2023)
7-144453630-C-T		Inborn genetic diseases	Uncertain significance (Jan 09, 2024)
7-144453632-G-A		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Feb 21, 2023)
7-144453635-C-T		Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Likely benign (Mar 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TPK1	protein_coding	protein_coding	ENST00000360057	8	384455

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0915	0.901	125733	0	14	125747	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.342	121	132	0.916	0.00000655	1594
Missense in Polyphen		47	51.835	0.90672		613
Synonymous	0.340	44	47.0	0.937	0.00000250	446
Loss of Function	2.33	4	13.1	0.306	5.50e-7	167

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000914	0.0000904
Ashkenazi Jewish	0.000100	0.0000992
East Asian	0.000163	0.000163
Finnish	0.0000468	0.0000462
European (Non-Finnish)	0.0000441	0.0000439
Middle Eastern	0.000163	0.000163
South Asian	0.0000670	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate. Can also catalyze the phosphorylation of pyrithiamine to pyrithiamine pyrophosphate. {ECO:0000269|PubMed:11342111}.
• Pathway: Thiamine metabolism - Homo sapiens (human);Thiamine Metabolism;thiamin salvage III;Vitamin B1 (thiamin) metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.134

Intolerance Scores

• loftool: 0.322
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.26

Haploinsufficiency Scores

• pHI: 0.866
• hipred: N
• hipred_score: 0.316
• ghis: 0.524

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.916

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tpk1

Gene ontology

• Biological process: thiamine metabolic process;thiamine diphosphate biosynthetic process;phosphorylation;thiamine-containing compound metabolic process
• Cellular component: cytosol
• Molecular function: thiamine diphosphokinase activity;ATP binding;kinase activity;thiamine binding