DNMT1

DNA methyltransferase 1, the group of 7BS C5-cytosine DNA/RNA methyltransferases|Zinc fingers CXXC-type

Basic information

Region (hg38): 19:10133341-10231286

Previous symbols: [ "DNMT" ]

Links

ENSG00000130816 ∙ NCBI:1786 ∙ OMIM:126375 ∙ HGNC:2976 ∙ Uniprot:P26358 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant cerebellar ataxia, deafness and narcolepsy (Strong), mode of inheritance: AD
• hereditary sensory neuropathy-deafness-dementia syndrome (Strong), mode of inheritance: AD
• autosomal dominant cerebellar ataxia, deafness and narcolepsy (Strong), mode of inheritance: AD
• autosomal dominant cerebellar ataxia, deafness and narcolepsy (Supportive), mode of inheritance: AD
• hereditary sensory neuropathy-deafness-dementia syndrome (Supportive), mode of inheritance: AD
• autosomal dominant cerebellar ataxia, deafness and narcolepsy (Strong), mode of inheritance: AD
• hereditary sensory neuropathy-deafness-dementia syndrome (Strong), mode of inheritance: AD
• autosomal dominant cerebellar ataxia, deafness and narcolepsy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neuropathy, hereditary sensory, type IE; Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant	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	Audiologic/Otolaryngologic; Neurologic	7898717; 10210919; 21532572; 22328086; 22338191; 23365052

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DNMT1 gene.

• Hereditary sensory neuropathy-deafness-dementia syndrome (1021 variants)
• not provided (349 variants)
• Inborn genetic diseases (118 variants)
• not specified (74 variants)
• Autosomal dominant cerebellar ataxia, deafness and narcolepsy (18 variants)
• Autosomal dominant cerebellar ataxia, deafness and narcolepsy;Hereditary sensory neuropathy-deafness-dementia syndrome (15 variants)
• Hereditary sensory neuropathy-deafness-dementia syndrome;Autosomal dominant cerebellar ataxia, deafness and narcolepsy (14 variants)
• Dementia, Deafness, and Sensory Neuropathy (6 variants)
• DNMT1-related condition (4 variants)
• Beckwith-Wiedemann syndrome (3 variants)
• Spastic ataxia (2 variants)
• DNMT1-Related Disorder (1 variants)
• Spastic paraparesis (1 variants)
• 7 conditions (1 variants)
• Dyssynergia (1 variants)
• Choreoathetosis;Paroxysmal choreoathetosis;Paroxysmal dyskinesia;Sleep abnormality;Chorea (1 variants)
• Charcot-Marie-Tooth disease (1 variants)
• Pituitary stalk interruption syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DNMT1 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			12	271	23	306
missense	2	9	394	27	6	438
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel			10			10
splice donor/acceptor (+/-2bp)	1		4	1		6
splice region			39	57	5	101
non coding			22	195	68	285
Total	3	9	444	494	97

Variants in DNMT1

This is a list of pathogenic ClinVar variants found in the DNMT1 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-10133344-G-C		Hereditary sensory neuropathy-deafness-dementia syndrome	Benign (Jan 13, 2018)
19-10133380-A-G		Hereditary sensory neuropathy-deafness-dementia syndrome	Benign (Jan 13, 2018)
19-10133393-A-G		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Jan 12, 2018)
19-10133414-C-T		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Jan 13, 2018)
19-10133456-C-G		Hereditary sensory neuropathy-deafness-dementia syndrome • Autosomal dominant cerebellar ataxia, deafness and narcolepsy;Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Oct 20, 2021)
19-10133502-A-C		Hereditary sensory neuropathy-deafness-dementia syndrome	Conflicting classifications of pathogenicity (Feb 01, 2023)
19-10133541-T-C		Dementia, Deafness, and Sensory Neuropathy	Uncertain significance (Jun 14, 2016)
19-10133633-T-G		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Jan 13, 2018)
19-10133638-C-T		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Jan 13, 2018)
19-10133649-G-A		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Jan 13, 2018)
19-10133649-G-T		Hereditary sensory neuropathy-deafness-dementia syndrome	Likely benign (Jan 13, 2018)
19-10133670-G-C			Uncertain significance (Jan 10, 2023)
19-10133671-T-C		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Jul 29, 2022)
19-10133672-C-G		Hereditary sensory neuropathy-deafness-dementia syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 17, 2023)
19-10133675-T-C		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Dec 19, 2023)
19-10133682-T-A		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Dec 10, 2022)
19-10133685-C-T		Hereditary sensory neuropathy-deafness-dementia syndrome	Likely benign (Feb 21, 2023)
19-10133688-C-T		Hereditary sensory neuropathy-deafness-dementia syndrome	Benign (Mar 08, 2023)
19-10133690-C-T		Hereditary sensory neuropathy-deafness-dementia syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jun 24, 2023)
19-10133699-T-C		Hereditary sensory neuropathy-deafness-dementia syndrome	Uncertain significance (Apr 04, 2022)
19-10133855-C-T			Benign (Jun 16, 2018)
19-10133878-G-A			Benign (Jun 26, 2018)
19-10134105-G-A			Benign (Jul 15, 2018)
19-10134199-T-C		Hereditary sensory neuropathy-deafness-dementia syndrome	Likely benign (May 03, 2023)
19-10134201-G-A		Hereditary sensory neuropathy-deafness-dementia syndrome	Likely benign (Dec 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DNMT1	protein_coding	protein_coding	ENST00000359526	41	97942

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.17e-10	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.99	537	976	0.550	0.0000663	10717
Missense in Polyphen		95	332.92	0.28535		3510
Synonymous	-0.360	408	399	1.02	0.0000298	3073
Loss of Function	8.21	7	91.9	0.0762	0.00000506	1078

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000125	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B 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. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). Promotes tumor growth (PubMed:24623306). {ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:18413740, ECO:0000269|PubMed:18754681, ECO:0000269|PubMed:24623306}.
• Disease: DISEASE: Neuropathy, hereditary sensory, 1E (HSN1E) [MIM:614116]: A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia. {ECO:0000269|PubMed:21532572}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant (ADCADN) [MIM:604121]: An autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy, cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression. {ECO:0000269|PubMed:22328086}. 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);S-Adenosylhomocysteine (SAH) Hydrolase Deficiency;Methionine Metabolism;Methionine Adenosyltransferase Deficiency;Glycine N-methyltransferase Deficiency;Hypermethioninemia;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type;Cystathionine Beta-Synthase Deficiency;Trans-sulfuration pathway;One Carbon Metabolism;Retinoblastoma (RB) in Cancer;Trans-sulfuration and one carbon metabolism;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;Regulation of retinoblastoma protein;PRC2 methylates histones and DNA (Consensus)

Recessive Scores

• pRec: 0.706

Intolerance Scores

• loftool: 0.0472
• rvis_EVS: -1.54
• rvis_percentile_EVS: 3.33

Haploinsufficiency Scores

• pHI: 0.750
• hipred: Y
• hipred_score: 0.831
• ghis: 0.672

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dnmt1
• Phenotype: growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); cellular phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; normal 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; pigmentation phenotype; neoplasm; digestive/alimentary 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); immune system phenotype

Zebrafish Information Network

• Gene name: dnmt1
• Affected structure: intestinal epithelial cell
• Phenotype tag: abnormal
• Phenotype quality: decreased height

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;DNA methylation;chromatin organization;Ras protein signal transduction;maintenance of DNA methylation;DNA methylation on cytosine within a CG sequence;positive regulation of gene expression;negative regulation of gene expression;gene silencing;DNA methylation involved in embryo development;negative regulation of gene expression, epigenetic;positive regulation of histone H3-K4 methylation;negative regulation of histone H3-K9 methylation;cellular response to amino acid stimulus;C-5 methylation of cytosine;positive regulation of methylation-dependent chromatin silencing;positive regulation of vascular smooth muscle cell proliferation;negative regulation of vascular associated smooth muscle cell apoptotic process;negative regulation of vascular smooth muscle cell differentiation involved in phenotypic switching
• Cellular component: nucleus;nucleoplasm;replication fork;pericentric heterochromatin
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;RNA binding;DNA (cytosine-5-)-methyltransferase activity;protein binding;zinc ion binding;methyl-CpG binding;DNA-methyltransferase activity;promoter-specific chromatin binding