DNMT3B

Chr 20Digenic dominantAR

DNA methyltransferase 3 beta

Also known as: FSHD4, ICF, ICF1, M.HsaIIIB

NCBI Gene: 1789 ENSG00000088305 UniProt: Q9UBC3 OMIM: 602900

The protein functions as a DNA methyltransferase that establishes de novo methylation patterns during development and is essential for genome-wide DNA methylation. Mutations cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome with autosomal recessive inheritance, and contribute to facioscapulohumeral muscular dystrophy 4 through digenic inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.375), reflecting its essential role in normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated. Mutations in this gene cause the immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. Eight alternatively spliced transcript variants have been described. The full length sequences of variants 4 and 5 have not been determined. [provided by RefSeq, May 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Facioscapulohumeral muscular dystrophy 4, digenicMIM #619478

Digenic dominant

Immunodeficiency-centromeric instability-facial anomalies syndrome 1MIM #242860

Clinical highlights

Gene-disease validity (ClinGen)

immunodeficiency-centromeric instability-facial anomalies syndrome 1 · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

225

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

LOF

Mechanism· G2P

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