TKFC

protein-coding

triokinase and FMN cyclase

Gene summary

This gene is a member of the family of dihydroxyacetone kinases, which have a protein structure distinct from other kinases. The product of this gene phosphorylates dihydroxyacetone, and also catalyzes the formation of riboflavin 4',5'-phosphate (aka cyclin FMN) from FAD. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2017]

Previous symbols:

MANE transcript

NM_015533.4

Inheritance

ClinVar variants

P:2U:114B:14

Top phenotype

Triokinase and FMN cyclase deficiency syndrome

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr11:61,333,220-61,353,295

External References & Databases

Ensembl (ENSG00000149476)

Transcript & Mutation Effects

hg38 • Region Span ~20.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

triokinase and FMN cyclase deficiency syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032927

Submitter: Ambry Genetics

triokinase and FMN cyclase deficiency syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032927

Submitter: G2P

Sengers syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008922

Submitter: Orphanet

inborn error of immunityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0003778

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Triokinase and FMN cyclase deficiency syndromeAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 32004446

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TKFC variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 109

not providedTotal: 12

Triokinase and FMN cyclase deficiency syndromeTotal: 7

TKFC deficiencyTotal: 2

Inborn errors of metabolismTotal: 2

Sengers syndromeTotal: 1

TKFC-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015533.4. 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	7 clinvar	2 clinvar	10
missense		2 clinvar	107 clinvar	5 clinvar		114
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	2	114	12	2	130

Highest pathogenic variant AF is 0.00001364243

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015533.4	RefSeq	NP_056348.2	17	MANE Select
ENST00000394900.8	Ensembl	ENSP00000378360.3	17	MANE Select
NM_001351976.2	RefSeq	NP_001338905.1	17	Standard
NM_001351977.2	RefSeq	NP_001338906.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fructose and mannose metabolism - Homo sapiens (human)
Glycerolipid metabolism - Homo sapiens (human)
RIG-I-like receptor signaling pathway - Homo sapiens (human)
RIG-I-like Receptor Signaling
Fructose metabolism

Biological Process

glycerol catabolic process
negative regulation of MDA-5 signaling pathway
cellular carbohydrate metabolic process
innate immune response
regulation of innate immune response

Molecular Function

glycerone kinase activity
protein binding
ATP binding
FAD-AMP lyase (cyclizing) activity
metal ion binding

Cellular Component

nucleus
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394900
Coding exons: 17
Length: 20086
Individuals with no LoFs: 125579
Homozygous LoFs: 0
Heterozygous LoFs: 169
Defined: 125748
p: 0.000672

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.395	352	373	0.943	0.0000239	3617
Missense (PolyPhen)		144	148.42	0.97022		1454
Synonymous	0.610	151	161	0.939	0.0000108	1288
Loss of Function	1.04	21	26.8	0.784	0.00000114	318

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0026	0.0026	notable
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0025	0.0025	notable
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00037	0.00032	rare
South Asian	0.0012	0.0011	notable
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate. Represses IFIH1-mediated cellular antiviral response (PubMed:17600090). {ECO:0000250|UniProtKB:F1RKQ4, ECO:0000250|UniProtKB:Q4KLZ6, ECO:0000269|PubMed:16289032, ECO:0000269|PubMed:17600090, ECO:0000269|PubMed:4688871}.;

Recessive Scores

pRec: 0.298

Intolerance Scores

RVIS EVS: -0.48
RVIS percentile EVS: 22.75

Essentials

Essential (gene trap): N