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

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 (38 variants)
• not provided (21 variants)
• Inborn genetic diseases (7 variants)
• Neurodevelopmental disorder (2 variants)
• EBV-positive nodal T- and NK-cell lymphoma (2 variants)
• Acute myeloid leukemia (2 variants)
• DNMT3A-related disorder (1 variants)
• Melanoma (1 variants)
• Lung adenocarcinoma (1 variants)
• See cases (1 variants)
• Myelodysplastic syndrome (1 variants)
• 6 conditions (1 variants)
• Intellectual disability (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.

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			5	121	4	130
missense	11	30	181	6		228
nonsense	19	5	1	1		26
start loss						0
frameshift	24	10	1			35
inframe indel			4			4
splice donor/acceptor (+/-2bp)	7	9	1			17
splice region		2	9	23	3	37
non coding	1		11	77	19	108
Total	62	54	204	205	23

Highest pathogenic variant AF is 0.000158

Variants in DNMT3A

This is a list of pathogenic ClinVar variants found in the DNMT3A region.

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

Position	Type	Phenotype	Significance	ClinVar
2-25234280-T-C		Tatton-Brown-Rahman overgrowth syndrome	Likely benign (Apr 10, 2023)
2-25234280-TAC-T			Uncertain significance (Nov 21, 2019)
2-25234288-C-T		Tatton-Brown-Rahman overgrowth syndrome	Likely benign (Jul 30, 2022)
2-25234289-G-A			Uncertain significance (Mar 18, 2022)
2-25234292-A-G		DNMT3A-related disorder	Pathogenic (Oct 16, 2020)
2-25234296-A-T		Intellectual disability	Likely pathogenic (Sep 10, 2020)
2-25234299-C-CCTT			Uncertain significance (Nov 17, 2022)
2-25234306-C-T		Tatton-Brown-Rahman overgrowth syndrome • DNMT3A-related disorder	Likely benign (Nov 19, 2023)
2-25234307-G-A		Autism spectrum disorder;Tatton-Brown-Rahman overgrowth syndrome • EBV-positive nodal T- and NK-cell lymphoma • Tatton-Brown-Rahman overgrowth syndrome	Pathogenic/Likely pathogenic (Mar 24, 2024)
2-25234308-G-A		Glioblastoma	Likely pathogenic (Jun 11, 2019)
2-25234311-C-G		Tatton-Brown-Rahman overgrowth syndrome	Uncertain significance (Sep 28, 2023)
2-25234313-A-G		Tatton-Brown-Rahman overgrowth syndrome	Pathogenic (Apr 01, 2014)
2-25234315-G-C		Tatton-Brown-Rahman overgrowth syndrome	Likely benign (Aug 24, 2023)
2-25234321-G-A		Tatton-Brown-Rahman overgrowth syndrome	Likely benign (Jan 19, 2024)
2-25234323-G-A		Tatton-Brown-Rahman overgrowth syndrome	Uncertain significance (Dec 13, 2022)
2-25234325-A-G		Neurodevelopmental disorder	Likely pathogenic (Jun 07, 2021)
2-25234330-T-C		Tatton-Brown-Rahman overgrowth syndrome • DNMT3A-related disorder	Benign/Likely benign (Jan 31, 2024)
2-25234336-G-A		Tatton-Brown-Rahman overgrowth syndrome • DNMT3A-related disorder	Likely benign (Dec 21, 2023)
2-25234340-C-T		Tatton-Brown-Rahman overgrowth syndrome	Pathogenic (Oct 03, 2023)
2-25234342-T-C		Tatton-Brown-Rahman overgrowth syndrome • DNMT3A-related disorder	Conflicting classifications of pathogenicity (Jan 22, 2024)
2-25234352-A-C		Acute myeloid leukemia	Uncertain significance (Mar 13, 2023)
2-25234359-T-G		Tatton-Brown-Rahman overgrowth syndrome	Likely benign (Nov 23, 2021)
2-25234360-C-T		Tatton-Brown-Rahman overgrowth syndrome • DNMT3A-related disorder	Likely benign (Jun 13, 2022)
2-25234360-CT-C			Likely pathogenic (Jun 29, 2018)
2-25234366-C-T		not specified • DNMT3A-related disorder • Tatton-Brown-Rahman overgrowth syndrome	Benign/Likely benign (Oct 31, 2022)

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