TET3

protein-coding

tet methylcytosine dioxygenase 3, the group of Zinc fingers CXXC-type|Tet methylcytosine dioxygenase family

Gene summary

Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; methyl-CpG binding activity; and zinc ion binding activity. Involved in positive regulation of transcription by RNA polymerase II and protein O-linked glycosylation. Predicted to be located in cytoplasm and male pronucleus. Predicted to be active in nucleus. Biomarker of esophagus squamous cell carcinoma. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001287491.2

Inheritance

AD, AR, SD

ClinVar variants

P:64U:380B:113

Top phenotype

Beck-Fahrner syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr2:73,984,910-74,108,177

External References & Databases

Ensembl (ENSG00000187605)

Transcript & Mutation Effects

hg38 • Region Span ~123.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Beck-Fahrner syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032922

Submitter: ClinGen

The *TET3* gene is located on chromosome 2 at 2p13.1 and encodes a methylcytosine dioxygenase that initiates DNA demethylation to regulate gene expression during early zygote formation, embryogenesis, and neuronal differentiation. *TET3* was first reported in relation to autosomal dominant Beck-Fahrner syndrome (BEFAHRS) in 2020 (Beck et al., PMID: 31928709). BEFAHRS is a developmental disorder characterized by global developmental delay with variable (mild to severe) intellectual disability, hypotonia, and craniofacial dysmorphisms. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the curation was split by inheritance pattern. This curation focuses on the relationship between *TET3* and autosomal dominant BEFAHRS. At least 12 unique variants (5 missense, 4 nonsense, 3 frameshift) have been reported in 12 probands in four publications (PMIDs: 31928709, 34750377, 34719681, 36192301) and are included in this curation. Nine out of the 12 variants were reported to occur de novo. This gene-disease relationship is supported by biochemical function study, functional alteration data, expression data and mouse models (PMIDs: 20639862, 34750377, 24838624, 21892189, 25640176). The mechanism of pathogenicity is reported to be dominant-negative. In summary, there is definitive evidence to support the relationship between *TET3* and autosomal dominant Beck-Fahrner syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date November 17, 2023 (SOP Version 10).

Beck-Fahrner syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032922

Submitter: G2P

Beck-Fahrner syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032922

Submitter: G2P

Beck-Fahrner syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032922

Submitter: ClinGen

The *TET3* gene is located on chromosome 2 at 2p13.1 and encodes a methylcytosine dioxygenase that initiates DNA demethylation to regulate gene expression during early zygote formation, embryogenesis, and neuronal differentiation. Variants in *TET3* have been reported in individuals with both autosomal recessive and autosomal dominant Beck-Fahrner syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive Beck-Fahrner syndrome and autosomal dominant Beck-Fahrner syndrome. The split curation for autosomal dominant Beck-Fahrner syndrome will be curated separately. curation was split by inheritance pattern. *TET3* was first reported in relation to autosomal recessive Beck-Fahrner syndrome (BEFAHRS) in 2018 (Santos-Cortez et al, PMID:30167849). BEFAHRS is a developmental disorder characterized by global developmental delay with variable (mild to severe) intellectual disability, hypotonia, and craniofacial dysmorphisms. At least 6 unique variants (5 missense, 1 nonsense) have been reported in 3 probands in three publications (PMIDs: 30167849, 31928709, 34719681) and are included in this curation. This gene-disease relationship is supported by biochemical function study, expression study, and rescue in a Xenopus model (PMIDs: 20639862, 24838624, 23217707). The mechanism of pathogenicity is currently unknown. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date November 17, 2023 (SOP Version 10). This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on the meeting date November 17, 2023 (SOP Version 10). It was reevaluated on May 1st, 2026. As a result of this reevaluation, the classification did not change (SOP Version 12).

Beck-Fahrner syndromeMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0032922

Submitter: Illumina

Beck-Fahrner syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032922

Submitter: Labcorp Genetics (formerly Invitae)

Beck-Fahrner syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032922

Submitter: PanelApp Australia

Beck-Fahrner syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032922

Submitter: PanelApp Australia

Beck-Fahrner syndromeMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0032922

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Beck-Fahrner syndromeAD/AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

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: 31928709

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TET3 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 366

Beck-Fahrner syndromeTotal: 126

TET3-related disorderTotal: 71

not specifiedTotal: 48

Inborn genetic diseasesTotal: 36

TET3 deficiencyTotal: 10

Neurodevelopmental disorderTotal: 3

Paediatric disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001287491.2. 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			4 clinvar	80 clinvar	9 clinvar	93
missense	1 clinvar	20 clinvar	359 clinvar	23 clinvar	1 clinvar	404
nonsense	6 clinvar	10 clinvar	4 clinvar			20
start loss						0
frameshift	4 clinvar	22 clinvar	8 clinvar			34
splice donor/acceptor (+/-2bp)		1 clinvar	5 clinvar			6
Total	11	53	380	103	10	557

Highest pathogenic variant AF is 0.000019721754

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001287491.2	RefSeq	NP_001274420.1	11	MANE Select
ENST00000409262.8	Ensembl	ENSP00000386869.3	11	MANE Select
NM_001366022.1	RefSeq	NP_001352951.1	11	Standard
ENST00000305799.8	Ensembl	ENSP00000307803.8	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MECP2 and Associated Rett Syndrome
TET1,2,3 and TDG demethylate DNA
Epigenetic regulation of gene expression
Gene expression (Transcription)

Biological Process

5-methylcytosine catabolic process
protein O-linked glycosylation
DNA demethylation of male pronucleus
positive regulation of transcription by RNA polymerase II
oxidation-reduction process

Molecular Function

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

Cellular Component

female pronucleus
male pronucleus
nucleus
chromosome
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409262
Coding exons: 9
Length: 105464
Individuals with no LoFs: 124619
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 124623
p: 0.0000160

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.88	732	986	0.742	0.0000607	10594
Missense (PolyPhen)		172	376.76	0.45653		4067
Synonymous	-1.04	460	432	1.06	0.0000294	3541
Loss of Function	6.75	1	55.1	0.0181	0.00000271	636

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000027	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 epigenetic chromatin reprogramming in the zygote following fertilization. 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 (By similarity). Selectively binds to the promoter region of target genes and contributes to regulate the expression of numerous developmental genes (PubMed:23217707). In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Participates in DNA demethylation in the paternal pronucleus by mediating conversion of 5mC into 5hmC, 5fC and 5caC. Does not mediate DNA demethylation of maternal pronucleus because of the presence of DPPA3/PGC7 on maternal chromatin that prevents TET3- binding to chromatin (By similarity). In addition to its role in DNA demethylation, also 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 (PubMed:23353889). {ECO:0000250|UniProtKB:Q8BG87, ECO:0000269|PubMed:23217707, ECO:0000269|PubMed:23353889}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.129
RVIS EVS: -1.51
RVIS percentile EVS: 3.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0980

Gene Damage Prediction

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