DNMT3A

DNA methyltransferase 3 alpha, the group of 7BS C5-cytosine DNA/RNA methyltransferases|MicroRNA protein coding host genes|PWWP domain containing

Basic information

Region (hg38): 2:25227855-25342590

Links

ENSG00000119772 ∙ NCBI:1788 ∙ OMIM:602769 ∙ HGNC:2978 ∙ Uniprot:Q9Y6K1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Heyn-Sproul-Jackson syndrome (Moderate), mode of inheritance: AD
• Tatton-Brown-Rahman overgrowth syndrome (Definitive), mode of inheritance: AD
• Tatton-Brown-Rahman overgrowth syndrome (Supportive), mode of inheritance: AD
• Heyn-Sproul-Jackson syndrome (Strong), mode of inheritance: AD
• Tatton-Brown-Rahman overgrowth syndrome (Strong), mode of inheritance: AD
• Tatton-Brown-Rahman overgrowth syndrome (Definitive), mode of inheritance: AD
• Heyn-Sproul-Jackson syndrome (Limited), mode of inheritance: AD
• Tatton-Brown-Rahman overgrowth syndrome (Definitive), mode of inheritance: AD
• Tatton-Brown-Rahman overgrowth syndrome (Definitive), mode of inheritance: AD
• Heyn-Sproul-Jackson syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Tatton-Brown-Rahman syndrome; Heyn-Sproul-Jackson syndrome	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	24614070; 30478443

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DNMT3A gene.

• Tatton-Brown-Rahman_overgrowth_syndrome (541 variants)
• Inborn_genetic_diseases (378 variants)
• not_provided (258 variants)
• DNMT3A-related_disorder (234 variants)
• not_specified (22 variants)
• Acute_myeloid_leukemia (19 variants)
• Heyn-Sproul-Jackson_syndrome (17 variants)
• Intellectual_disability (8 variants)
• EBV-positive_nodal_T-_and_NK-cell_lymphoma (7 variants)
• Autism_spectrum_disorder (6 variants)
• Neurodevelopmental_disorder (4 variants)
• See_cases (4 variants)
• Hereditary_pheochromocytoma-paraganglioma (3 variants)
• Early_T_cell_progenitor_acute_lymphoblastic_leukemia (1 variants)
• Glioblastoma (1 variants)
• Clonal_Cytopenia_of_Undetermined_Significance (1 variants)
• Multiple_myeloma (1 variants)
• Rare_genetic_intellectual_disability (1 variants)
• Neonatal_hypotonia (1 variants)
• Large_for_gestational_age (1 variants)
• Obesity (1 variants)
• Craniosynostosis_syndrome (1 variants)
• Melanoma (1 variants)
• Global_developmental_delay (1 variants)
• Specific_learning_disability (1 variants)
• Abnormality_of_the_nervous_system (1 variants)
• Optic_disc_pallor (1 variants)
• Malignant_lymphoma,_large_B-cell,_diffuse (1 variants)
• Hypoparathyroidism (1 variants)
• Myeloproliferative_disorder (1 variants)
• Macrocephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DNMT3A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000022552.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	12	311	1	325
missense	21	60	359	13		453
nonsense	30	9	6	1		46
start loss						0
frameshift	46	16	3			65
splice donor/acceptor (+/-2bp)	9	14	14			37
Total	106	100	394	325	1

Highest pathogenic variant AF is 0.0002648167

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DNMT3A	protein_coding	protein_coding	ENST00000264709	22	109615

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.35e-39	4.27e-8	125617	0	131	125748	0.000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.45	339	571	0.594	0.0000365	5830
Missense in Polyphen		152	223.59	0.67982		2353
Synonymous	0.627	222	234	0.948	0.0000162	1751
Loss of Function	-1.52	52	41.4	1.25	0.00000209	493

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000811	0.000786
Ashkenazi Jewish	0.000799	0.000794
East Asian	0.000613	0.000598
Finnish	0.000372	0.000370
European (Non-Finnish)	0.000685	0.000677
Middle Eastern	0.000613	0.000598
South Asian	0.000262	0.000261
Other	0.000328	0.000326

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. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. Plays a role in paternal and maternal imprinting. Required for methylation of most imprinted loci in germ cells. Acts as a transcriptional corepressor for ZBTB18. Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. Can actively repress transcription through the recruitment of HDAC activity. {ECO:0000269|PubMed:16357870}.
• Disease: DISEASE: Tatton-Brown-Rahman syndrome (TBRS) [MIM:615879]: An overgrowth syndrome characterized by a distinctive facial appearance, tall stature and intellectual disability. Facial gestalt is characterized by a round face, heavy horizontal eyebrows and narrow palpebral fissures. Less common features include atrial septal defects, seizures, umbilical hernia, and scoliosis. {ECO:0000269|PubMed:24614070, ECO:0000269|PubMed:27317772, ECO:0000269|PubMed:27701732}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cysteine and methionine metabolism - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex;One carbon metabolism and related pathways;DNA methylation;Epigenetic regulation of gene expression;Gene expression (Transcription);RMTs methylate histone arginines;Chromatin modifying enzymes;Methionine and cysteine metabolism;Chromatin organization;Validated targets of C-MYC transcriptional repression;PRC2 methylates histones and DNA (Consensus)

Recessive Scores

• pRec: 0.415

Intolerance Scores

• loftool: 0.150
• rvis_EVS: -1.13
• rvis_percentile_EVS: 6.48

Haploinsufficiency Scores

• pHI: 0.887
• hipred: Y
• hipred_score: 0.685
• ghis: 0.618

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dnmt3a
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; hematopoietic 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); reproductive system 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); homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;mitotic cell cycle;DNA methylation;methylation-dependent chromatin silencing;regulation of gene expression by genetic imprinting;spermatogenesis;aging;response to ionizing radiation;response to lead ion;positive regulation of cell death;neuron differentiation;response to estradiol;response to vitamin A;response to cocaine;DNA methylation involved in embryo development;DNA methylation involved in gamete generation;negative regulation of gene expression, epigenetic;cellular response to amino acid stimulus;cellular response to ethanol;cellular response to hypoxia;C-5 methylation of cytosine;hepatocyte apoptotic process
• Cellular component: chromosome, centromeric region;euchromatin;XY body;nucleus;nucleoplasm;nuclear heterochromatin;cytoplasm;nuclear matrix
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;chromatin binding;transcription corepressor activity;DNA (cytosine-5-)-methyltransferase activity;protein binding;transcription factor binding;DNA-methyltransferase activity;identical protein binding;metal ion binding