TET3

Chr 2ADAR

tet methylcytosine dioxygenase 3

Also known as: BEFAHRS, hCG_40738

NCBI Gene: 200424 ENSG00000187605 UniProt: O43151 OMIM: 613555

TET3 encodes a dioxygenase that catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine and plays a key role in DNA demethylation and epigenetic chromatin reprogramming, particularly in the paternal pronucleus following fertilization. Mutations cause Beck-Fahrner syndrome with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.086), indicating that complete loss of function is likely not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.091 OMIM phenotype

Clinical Summary— TET3

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Gene-Disease Validity (ClinGen)

Beck-Fahrner syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

58 unique Pathogenic / Likely Pathogenic· 319 VUS of 498 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TET3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 6.75

OE 0.02 (0.01–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.88Z-score

OE missense 0.74 (0.70–0.79)

732 obs / 986.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.09)

0≤0.351.4

Missense OE?0.74 (0.70–0.79)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 1 / 55.1Missense obs/exp: 732 / 986.4Syn Z: -1.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTET3-related DNA demethylation disorderLOFAD

strongTET3-related DNA demethylation disorderLOFAR

This gene — mechanism propensity

0.15100th %ile

GOF

0.1699th %ile

LOF

0.88top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 67% of P/LP variants are LoF · LOEUF 0.09

Literature Evidence

LOFTET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31928709 ↗

ClinVar Variant Classifications

498 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic45

VUS319

Likely Benign74

Benign15

Conflicting15

Pathogenic

Likely Pathogenic

319

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	1	3	0	13
Likely Pathogenic	30	14	1	0	45
VUS	9	285	22	3	319
Likely Benign	0	15	1	58	74
Benign	0	2	3	10	15
Conflicting	—				15
Total	48	317	30	71	481

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap TET3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →