TET1

protein-coding

tet methylcytosine dioxygenase 1, the group of Zinc fingers CXXC-type|Tet methylcytosine dioxygenase family

Gene summary

DNA methylation is an epigenetic mechanism that is important for controlling gene expression. The protein encoded by this gene is a demethylase that belongs to the TET (ten-eleven translocation) family. Members of the TET protein family play a role in the DNA methylation process and gene activation. [provided by RefSeq, Sep 2015]

Previous symbols:

CXXC6

MANE transcript

NM_030625.3

Inheritance

—

ClinVar variants

U:223B:45

Top phenotype

TET1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr10:68,560,337-68,694,487

External References & Databases

Ensembl (ENSG00000138336)

Transcript & Mutation Effects

hg38 • Region Span ~134.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TET1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 216

not providedTotal: 26

TET1-related disorderTotal: 21

Neurodevelopmental delayTotal: 1

Hearing impairmentTotal: 1

HypothyroidismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030625.3. 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	12 clinvar	7 clinvar	20
missense			213 clinvar	19 clinvar	7 clinvar	239
nonsense			2 clinvar			2
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	223	31	14	268

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030625.3	RefSeq	NP_085128.2	11	MANE Select
ENST00000373644.5	Ensembl	ENSP00000362748.4	11	MANE Select
NM_001406365.1	RefSeq	NP_001393294.1	12	Standard
NM_001406367.1	RefSeq	NP_001393296.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

The oncogenic action of Succinate
The oncogenic action of Fumarate
The oncogenic action of 2-hydroxyglutarate
The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria
The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria

Biological Process

inner cell mass cell differentiation
5-methylcytosine catabolic process
chromatin organization
protein O-linked glycosylation
positive regulation of cell population proliferation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
iron ion binding
zinc ion binding
methylcytosine dioxygenase activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373644
Coding exons: 11
Length: 133827
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125744
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.62	970	1.12e+3	0.864	0.0000581	13990
Missense (PolyPhen)		136	239.78	0.56719		3015
Synonymous	0.0692	428	430	0.996	0.0000236	4247
Loss of Function	7.32	7	75.7	0.0925	0.00000426	989

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5- hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Also mediates subsequent conversion of 5hmC into 5- formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, plays a more general role in chromatin regulation. Preferentially binds to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. Also involved in transcription repression of a subset of genes through recruitment of transcriptional repressors to promoters. Involved in the balance between pluripotency and lineage commitment of cells it plays a role in embryonic stem cells maintenance and inner cell mass cell specification. Plays an important role in the tumorigenicity of glioblastoma cells. TET1-mediated production of 5hmC acts as a recruitment signal for the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of genes involved in glioblastomagenesis (PubMed:25284789). {ECO:0000269|PubMed:12124344, ECO:0000269|PubMed:19372391, ECO:0000269|PubMed:19372393, ECO:0000269|PubMed:21496894, ECO:0000269|PubMed:21778364, ECO:0000269|PubMed:25284789}.;
Disease: DISEASE: Note=A chromosomal aberration involving TET1 may be a cause of acute leukemias (PubMed:12646957). Translocation t(10;11)(q22;q23) with KMT2A/MLL1. This is a rare chromosomal translocation 5' KMT2A/MLL1-TET1 3' (PubMed:12124344, PubMed:12646957). {ECO:0000269|PubMed:12124344, ECO:0000269|PubMed:12646957}.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.247
RVIS EVS: 0.4
RVIS percentile EVS: 76.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.194

Gene Damage Prediction

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