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DNMT3B
DNA methyltransferase 3 beta
DNMT3B is located on the long (q) arm of chromosome 20, at band 20q11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
DNMT3B belongs to a family of enzymes responsible for DNA methylation, a chemical modification that influences gene activity without altering the underlying DNA sequence. The protein encoded by this gene works alongside other methyltransferases to establish methylation patterns during embryonic development and to maintain methylation at specific genomic regions throughout life.
Alterations in DNMT3B can disrupt normal methylation patterns, leading to inappropriate gene expression and chromosome instability. These disruptions particularly affect the immune system and developmental processes, resulting in a rare inherited condition characterised by immunodeficiency and distinctive facial features.
What the gene does
The DNMT3B protein catalyses the addition of methyl groups to cytosine bases in DNA, specifically at CpG dinucleotides where a cytosine nucleotide is followed by a guanine. This methylation typically silences gene expression by preventing transcription factors from accessing DNA or by recruiting proteins that compact chromatin structure.
DNMT3B plays a particularly important role in establishing de novo methylation patterns, meaning it can add methyl groups to previously unmethylated DNA rather than simply copying existing patterns. The enzyme shows preferential activity at pericentromeric satellite DNA repeats, the repetitive sequences flanking chromosome centromeres. Proper methylation of these regions is essential for chromosome condensation and segregation during cell division.
During embryonic development, DNMT3B works coordinately with DNMT3A to establish tissue-specific methylation patterns that determine cell fate. The enzyme also contributes to genomic imprinting, the process by which certain genes are expressed from only one parental chromosome based on methylation status.
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Chromosome location
DNMT3B is located on the long arm of chromosome 20 at position 11.21, designated as 20q11.21. The gene spans a substantial genomic region and produces multiple transcript variants through alternative splicing, generating protein isoforms with varying enzymatic activities and tissue distributions.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in DNMT3B typically result in reduced or absent enzyme activity, disrupting normal DNA methylation patterns throughout the genome. Most disease-causing variants are missense changes affecting the catalytic domain or nonsense variants that truncate the protein. The loss of DNMT3B function leads to hypomethylation, particularly at pericentromeric satellite repeats, causing chromosome instability.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1807G>A | p.Ala603Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
c.1838T>C | p.Val613Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
c.1957G>A | p.Asp653Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
c.2177T>G | p.Val726Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
c.2348_2349del | p.Gln783fs | Pathogenic/Likely pathogenic | ★★☆☆ | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 |
c.2421-11G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 |
c.2452G>A | p.Val818Met | Pathogenic | ★★☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
c.2476C>T | p.Arg826Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 |
c.8del | p.Gly3fs | Pathogenic | ★☆☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
c.93del | p.Ser32fs | Pathogenic | ★☆☆☆ | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in DNMT3B cause immunodeficiency-centromeric instability-facial anomalies syndrome, commonly known as ICF syndrome. This rare autosomal recessive condition is characterised by a variable immunodeficiency affecting antibody production, unusual facial features, and chromosomal abnormalities visible under microscopy. The immunodeficiency component typically manifests as recurrent respiratory and gastrointestinal infections due to reduced immunoglobulin levels. Some affected individuals also experience intellectual disability and developmental delays, though the severity varies considerably between cases.
No disease links recorded for this gene in our reference set.
UK clinical status
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is DNA methylation and why does it matter?
DNA methylation is the addition of small chemical groups (methyl groups) to DNA that helps control which genes are switched on or off in different cell types. This process does not change the DNA sequence itself but influences how cells read and use genetic instructions, playing a crucial role in normal development and cellular function.
How common are DNMT3B variants?
Pathogenic variants in DNMT3B are rare, with ICF syndrome affecting fewer than 1 in 1,000,000 individuals worldwide. The condition follows an autosomal recessive inheritance pattern, meaning affected individuals inherit altered copies from both parents.
Can DNMT3B variants be detected through standard genetic testing?
DNMT3B variants can be identified through comprehensive gene sequencing panels that examine DNA methylation-related genes or through broader genomic sequencing approaches. Testing is typically pursued when clinical features suggest ICF syndrome or when investigating unexplained immunodeficiency with chromosome abnormalities.