DNMT3B

DNA methyltransferase 3 beta, the group of PWWP domain containing|7BS C5-cytosine DNA/RNA methyltransferases

Basic information

Region (hg38): 20:32762384-32809359

Links

ENSG00000088305 ∙ NCBI:1789 ∙ OMIM:602900 ∙ HGNC:2979 ∙ Uniprot:Q9UBC3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency-centromeric instability-facial anomalies syndrome 1 (Definitive), mode of inheritance: AR
• immunodeficiency-centromeric instability-facial anomalies syndrome 1 (Definitive), mode of inheritance: AR
• immunodeficiency-centromeric instability-facial anomalies syndrome (Supportive), mode of inheritance: AR
• immunodeficiency-centromeric instability-facial anomalies syndrome 1 (Strong), mode of inheritance: AR
• immunodeficiency-centromeric instability-facial anomalies syndrome 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency-centromeric instability-facial anomalies syndrome 1	AR	Allergy/Immunology/Infectious	Though the disorder may be clinically recognizable in many individuals, immunoglobulin supplementation can be beneficial, as can prophylaxis and early and aggressive treatment of infections	Allergy/Immunology/Infectious; Neurologic	8076938; 10555141; 10647011; 11102980; 17893117

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DNMT3B gene.

• Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (536 variants)
• Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (128 variants)
• not provided (41 variants)
• Inborn genetic diseases (36 variants)
• not specified (12 variants)
• DNMT3B-related condition (3 variants)
• Immunodeficiency-centromeric instability-facial anomalies syndrome 1;Facioscapulohumeral muscular dystrophy 4, digenic (2 variants)
• Kabuki syndrome 1 (1 variants)
• Facioscapulohumeral muscular dystrophy 4, digenic (1 variants)
• Facioscapulohumeral muscular dystrophy 4, digenic;Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (1 variants)
• Non-obstructive azoospermia (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DNMT3B gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	150	9	167
missense	3	8	214	2	2	229
nonsense	6					6
start loss						0
frameshift	2	2				4
inframe indel			3			3
splice donor/acceptor (+/-2bp)		2				2
splice region			20	29	5	54
non coding		1	42	72	12	127
Total	11	13	267	224	23

Highest pathogenic variant AF is 0.0000197

Variants in DNMT3B

This is a list of pathogenic ClinVar variants found in the DNMT3B region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-32762403-G-A		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762432-C-T		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Benign (Jan 13, 2018)
20-32762439-C-A		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762442-C-T		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 12, 2018)
20-32762472-G-C		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762482-C-A		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 12, 2018)
20-32762494-C-T		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762543-A-C		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762601-C-T		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762644-C-G		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 13, 2018)
20-32762685-C-T		Immunodeficiency-centromeric instability-facial anomalies syndrome 1	Uncertain significance (Jan 12, 2018)
20-32780142-C-T		not specified	Benign (Mar 28, 2016)
20-32780333-G-C		Inborn genetic diseases	Uncertain significance (Aug 30, 2021)
20-32780337-C-G		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Uncertain significance (Aug 30, 2021)
20-32780353-A-G		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Dec 31, 2023)
20-32780362-C-T		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Jan 16, 2024)
20-32780363-G-C		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Uncertain significance (Aug 23, 2022)
20-32780365-C-T		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency • Immunodeficiency-centromeric instability-facial anomalies syndrome 1 • DNMT3B-related disorder	Benign/Likely benign (Feb 01, 2024)
20-32780366-G-A		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 12, 2023)
20-32780368-C-T		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Sep 03, 2023)
20-32780380-C-G		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Uncertain significance (Dec 24, 2021)
20-32780380-C-T		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Jan 28, 2024)
20-32780383-G-A		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Jun 24, 2022)
20-32780383-G-C		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Oct 22, 2023)
20-32780383-G-T		Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	Likely benign (Dec 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DNMT3B	protein_coding	protein_coding	ENST00000328111	22	46972

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.200	0.800	125731	0	17	125748	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.50	418	514	0.814	0.0000358	5565
Missense in Polyphen		192	300.35	0.63925		3376
Synonymous	-0.163	214	211	1.01	0.0000156	1669
Loss of Function	5.26	13	55.2	0.236	0.00000383	562

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000883	0.0000879
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co- repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing (By similarity). In association with DNMT1 and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Function as transcriptional corepressor by associating with ZHX1. Required for DUX4 silencing in somatic cells (PubMed:27153398). {ECO:0000250, ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:17303076, ECO:0000269|PubMed:18413740, ECO:0000269|PubMed:18567530, ECO:0000269|PubMed:27153398}.
• Disease: DISEASE: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (ICF1) [MIM:242860]: A rare disorder characterized by a variable immunodeficiency resulting in recurrent infections, facial anomalies, and branching of chromosomes 1, 9, and 16. Other variable symptoms include growth retardation, failure to thrive, and psychomotor retardation. Laboratory studies show limited hypomethylation of DNA in a small fraction of the genome in some, but not all, patients. {ECO:0000269|PubMed:10555141, ECO:0000269|PubMed:10588719, ECO:0000269|PubMed:10647011, ECO:0000269|PubMed:11102980, ECO:0000269|PubMed:15580563, ECO:0000269|PubMed:21120685, ECO:0000269|PubMed:27734333}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Facioscapulohumeral muscular dystrophy 2 (FSHD2) [MIM:158901]: A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. {ECO:0000269|PubMed:27153398}. Note=The gene represented in this entry may act as a disease modifier. DNMT3B mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.
• Pathway: Cysteine and methionine metabolism - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);miR-targeted genes in lymphocytes - TarBase;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;Mesodermal Commitment Pathway;Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex;NoRC negatively regulates rRNA expression;Negative epigenetic regulation of rRNA expression;DNA methylation;Epigenetic regulation of gene expression;Gene expression (Transcription);Methionine and cysteine metabolism;PRC2 methylates histones and DNA (Consensus)

Recessive Scores

• pRec: 0.0949

Intolerance Scores

• loftool: 0.00992
• rvis_EVS: -1.7
• rvis_percentile_EVS: 2.54

Haploinsufficiency Scores

• pHI: 0.642
• hipred: Y
• hipred_score: 0.770
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dnmt3b
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; skeleton phenotype; embryo phenotype; liver/biliary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; neoplasm; endocrine/exocrine gland phenotype; craniofacial phenotype; cellular phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: dnmt3bb.2
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;response to hypoxia;DNA methylation;response to toxic substance;response to ionizing radiation;positive regulation of gene expression;response to activity;response to caffeine;response to estradiol;response to vitamin A;response to cocaine;positive regulation of neuron differentiation;negative regulation of gene expression, epigenetic;positive regulation of histone H3-K4 methylation;negative regulation of histone H3-K9 methylation;cellular response to hyperoxia;cellular response to dexamethasone stimulus;C-5 methylation of cytosine
• Cellular component: nucleus;nucleoplasm;intracellular membrane-bounded organelle
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;chromatin binding;transcription corepressor activity;DNA (cytosine-5-)-methyltransferase activity;protein binding;DNA-methyltransferase activity;histone deacetylase binding;metal ion binding