EHMT1

protein-coding

euchromatic histone lysine methyltransferase 1, the group of Lysine methyltransferases|Ankyrin repeat domain containing|SET domain containing

Gene summary

The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

Previous symbols:

EHMT1-IT1

MANE transcript

NM_024757.5

Inheritance

ClinVar variants

P:271U:687B:1044

Top phenotype

Kleefstra syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr9:137,618,992-137,870,016

External References & Databases

Ensembl (ENSG00000181090)

Transcript & Mutation Effects

hg38 • Region Span ~251.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kleefstra syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0027407

Submitter: Ambry Genetics

Kleefstra syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012455

Submitter: ClinGen

*EHMT1* was first reported in relation to autosomal dominant Kleefstra syndrome in 2005 (Kleefstra et al., PMID: 15805155). *EHMT1* encodes a histone methyltransferase that regulates gene expression. Kleefstra syndrome is characterized by developmental delay, limited or absent speech, intellectual disability, autism or autistic-like features, hypotonia, and distinctive facial features. Additional findings may include heart abnormalities, kidney defects, and epilepsy. Though this evaluation focuses on sequence-level variation in the *EHMT1* gene, Kleefstra syndrome is also caused by larger deletions of the 9q34 region; these deletions vary in size and have variable breakpoints, but all include at least part of the *EHMT1* gene. Ten variants (frameshift, nonsense, splice, missense) that have been reported in 10 probands in three publications (PMIDs: 22670141, 27651234, 28361100) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by mouse, drosophila and cell culture models, and functional studies implicating variants in this gene in neuronal dysfunction. In summary, there is definitive evidence supporting the relationship between *EHMT1* and autosomal dominant Kleefstra syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 6, 2018 (SOP Version 5).

Kleefstra syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0027407

Submitter: G2P

Kleefstra syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0027407

Submitter: PanelApp Australia

Kleefstra syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0027407

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Kleefstra syndrome 1AD

Manifestation: Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 16826528; 19264732; 21910222; 22670143; 23232695

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EHMT1 variants in ClinVar

22 Conditions Cataloged

Kleefstra syndrome 1Total: 2042

not providedTotal: 662

Inborn genetic diseasesTotal: 359

not specifiedTotal: 215

EHMT1-related disorderTotal: 114

Intellectual disabilityTotal: 15

EHMT1-related disordersTotal: 12

Kleefstra syndromeTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024757.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	15 clinvar	491 clinvar	42 clinvar	550
missense	18 clinvar	21 clinvar	646 clinvar	434 clinvar	75 clinvar	1194
nonsense	47 clinvar	12 clinvar	4 clinvar			63
start loss			2 clinvar	1 clinvar		3
frameshift	100 clinvar	23 clinvar	9 clinvar			132
splice donor/acceptor (+/-2bp)	25 clinvar	23 clinvar	11 clinvar	1 clinvar		60
Total	190	81	687	927	117	2002

Highest pathogenic variant AF is 0.000037836366

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 106 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024757.5	RefSeq	NP_079033.4	27	MANE Select
ENST00000460843.6	Ensembl	ENSP00000417980.1	27	MANE Select
NM_001145527.2	RefSeq	NP_001138999.1	16	Standard
NM_001354259.2	RefSeq	NP_001341188.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Longevity regulating pathway - Homo sapiens (human)
miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

negative regulation of transcription by RNA polymerase II
DNA methylation
chromatin organization
histone methylation
peptidyl-lysine monomethylation

Molecular Function

p53 binding
protein binding
methyltransferase activity
zinc ion binding
protein-lysine N-methyltransferase activity

Cellular Component

nucleus
nucleoplasm
chromosome
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000460843
Coding exons: 27
Length: 251025
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125748
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.16	713	806	0.885	0.0000565	8520
Missense (PolyPhen)		167	302.96	0.55122		3167
Synonymous	-3.17	425	350	1.22	0.0000298	2528
Loss of Function	7.42	1	66.1	0.0151	0.00000385	742

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. During G0 phase, it probably contributes to silencing of MYC- and E2F-responsive genes, suggesting a role in G0/G1 transition in cell cycle. In addition to the histone methyltransferase activity, also methylates non- histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. {ECO:0000269|PubMed:12004135, ECO:0000269|PubMed:20118233}.;
Disease: DISEASE: Kleefstra syndrome 1 (KLEFS1) [MIM:610253]: A form of Kleefstra syndrome, an autosomal dominant disease characterized by variable mental retardation, psychomotor developmental delay, seizures, behavioral abnormalities, and facial dysmorphisms. KLEFS1 patients additionally manifest brachy(micro)cephaly, congenital heart defects, and urogenital defects. {ECO:0000269|PubMed:16826528, ECO:0000269|PubMed:19264732}. Note=The disease is caused by mutations affecting the gene represented in this entry (PubMed:16826528). The syndrome can be either caused by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene or by a submicroscopic 9q34.3 deletion. Although it is not known if and to what extent other genes in the 9q34.3 region contribute to the syndrome observed in deletion cases, EHMT1 seems to be the major determinant of the core disease phenotype (PubMed:19264732). {ECO:0000269|PubMed:16826528, ECO:0000269|PubMed:19264732}.;

Recessive Scores

pRec: 0.146

Intolerance Scores

LoFtool: 0.0183
RVIS EVS: -1.58
RVIS percentile EVS: 3.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.949

Gene Damage Prediction

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