GeneBe

MECOM

protein-coding

MDS1 and EVI1 complex locus, the group of PR/SET domain family|Lysine methyltransferases|Zinc fingers C2H2-type

Gene summary

The protein encoded by this gene is a transcriptional regulator and oncoprotein that may be involved in hematopoiesis, apoptosis, development, and cell differentiation and proliferation. The encoded protein can interact with CTBP1, SMAD3, CREBBP, KAT2B, MAPK8, and MAPK9. This gene can undergo translocation with the AML1 gene, resulting in overexpression of this gene and the onset of leukemia. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

Previous symbols:
  • MDS1
  • EVI1

MANE transcript

NM_004991.4

Inheritance

AD

ClinVar variants

P:39U:1225B:625

Top phenotype

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr3:169,083,499-169,663,775

External References & Databases

Ensembl (ENSG00000085276)NCBI Gene (2122)OMIM (165215)HGNC:3498GenCCUniProt (Q03112)AlphaFoldClinVar (MECOM)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~580.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011555

Submitter: Orphanet

radioulnar synostosis with amegakaryocytic thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014758

Submitter: G2P

radioulnar synostosis with amegakaryocytic thrombocytopenia 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014758

Submitter: Ambry Genetics

radioulnar synostosis with amegakaryocytic thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014758

Submitter: Labcorp Genetics (formerly Invitae)

radioulnar synostosis with amegakaryocytic thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014758

Submitter: PanelApp Australia

MECOM-associated syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100458

Submitter: ClinGen

MECOM was first reported in relation to Autosomal dominant MECOM-associated syndrome in 2015 (Niihori et al., PMID:26581901). This is a syndromic disease with a variable phenotypic pattern, ranging from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormalities. The clinical picture can also include clinodactyly, cardiac and renal malformations, B-cell deficiency, amegakaryocytic thrombocytopenia, and presenile hearing loss. MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis. The MECOM locus encodes a number of differentially spliced transcripts yielding the MDS1, MDS1-EVI1, and EVI1 protein isoforms. At least 10 missense variants and 5 predicted null variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 16 probands in 4 publications (PMID: 26581901, 29519864, 29540340, 29097497). The mechanism for disease may be haploinsufficiency. This gene-disease association is supported by expression studies consistent with roles in bone marrow (PMID: 22084405) and limb development (PMID: 1893871) and mouse models with partial recapitulation of phenotypes (PMIDs: 24586749, 17029558). In summary, MECOM is definitively associated with Autosomal Dominant MECOM-associated syndrome. This has been repeatedly demonstrated in research and has been upheld over time.

Clinical Genomic Database (CGD)

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2AD

Manifestation: Allergy/Immunology/Infectious; Hematologic; Musculoskeletal

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: The condition involves bone marrow failure, and awareness may allow prompt management of hematologic complications as well as complications related to susceptibility to infections; HSCT has been described

Refs: 20091385; 26581901Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MECOM variants in ClinVar

16 Conditions Cataloged
Inborn genetic diseasesTotal: 1674
not providedTotal: 504
not specifiedTotal: 110
MECOM-related disorderTotal: 74
Radioulnar synostosis with amegakaryocytic thrombocytopenia 2Total: 35
MECOM-associated syndromeTotal: 12
Radioulnar synostosisTotal: 7
ThrombocytopeniaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004991.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
572
clinvar
2
clinvar
 577
missense
7
clinvar
15
clinvar
1213
clinvar
51
clinvar
 1286
nonsense
5
clinvar
3
clinvar
3
clinvar
 11
start loss
0
frameshift
4
clinvar
2
clinvar
 6
splice donor/acceptor (+/-2bp)
2
clinvar
1
clinvar
6
clinvar
 9
Total1821122562321889

Highest pathogenic variant AF is 0.000014443806

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004991.4RefSeqNP_004982.217MANE Select
ENST00000651503.2EnsemblENSP00000498411.117MANE Select
NM_001105077.4RefSeqNP_001098547.316Standard
NM_001105078.4RefSeqNP_001098548.214Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mecomDanio rerio

Structure: ventral wall of dorsal aorta

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Chronic myeloid leukemia - Homo sapiens (human)
  • MAPK signaling pathway - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)
  • White fat cell differentiation
  • White fat cell differentiation

Biological Process

  • regulation of transcription by RNA polymerase II
  • apoptotic process
  • cell differentiation
  • histone lysine methylation
  • negative regulation of programmed cell death

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA binding
  • DNA-binding transcription factor activity
  • protein binding
  • histone-lysine N-methyltransferase activity

Cellular Component

  • histone deacetylase complex
  • nucleus
  • nucleoplasm
  • cytosol
  • nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264674
Coding exons
16
Length
580120
Individuals with no LoFs
125726
Homozygous LoFs
0
Heterozygous LoFs
7
Defined
125733
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.624966080.8150.00003167461
Missense (PolyPhen)177255.630.692393150
Synonymous-1.282522271.110.00001312018
Loss of Function6.02246.10.04330.00000216626

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Isoform 1: Functions as a transcriptional regulator binding to DNA sequences in the promoter region of target genes and regulating positively or negatively their expression. Oncogene which plays a role in development, cell proliferation and differentiation. May also play a role in apoptosis through regulation of the JNK and TGF-beta signaling. Involved in hematopoiesis. {ECO:0000269|PubMed:10856240, ECO:0000269|PubMed:11568182, ECO:0000269|PubMed:15897867, ECO:0000269|PubMed:16462766, ECO:0000269|PubMed:19767769, ECO:0000269|PubMed:9665135}.;
Disease
DISEASE: Note=A chromosomal aberration involving EVI1 is a cause of chronic myelogenous leukemia (CML). Translocation t(3;21)(q26;q22) with RUNX1/AML1. {ECO:0000269|PubMed:8313895}.; DISEASE: Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 (RUSAT2) [MIM:616738]: An autosomal dominant disease characterized by proximal fusion of the radius and ulna resulting in extremely limited pronation and supination of the forearm, and congenital thrombocytopenia that progresses to pancytopenia. {ECO:0000269|PubMed:26581901}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving MDS1 is found in a form of acute myeloid leukemia (AML). Translocation t(3;21) with AML1. {ECO:0000269|PubMed:8643684}.;

Recessive Scores

pRec
0.302

Intolerance Scores

RVIS EVS
-0.99
RVIS percentile EVS
8.56

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.450

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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