MECOM

Chr 3AD

MDS1 and EVI1 complex locus

Also known as: AML1-EVI-1, EVI1, KMT8E, MDS1, MDS1-EVI1, PRDM3, RUSAT2

NCBI Gene: 2122 ENSG00000085276 UniProt: Q03112 OMIM: 165215

MECOM encodes a transcriptional regulator that controls gene expression and is involved in hematopoiesis, development, cell proliferation and differentiation. Mutations cause radioulnar synostosis with amegakaryocytic thrombocytopenia, which follows autosomal dominant inheritance and presents with limb malformations and severe bleeding due to low platelet counts. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that haploinsufficiency is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

GOFmechanismADLOEUF 0.141 OMIM phenotype

Clinical Summary— MECOM

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Gene-Disease Validity (ClinGen)

MECOM-associated syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.14LOEUF

pLI 1.000

Z-score 6.02

OE 0.04 (0.02–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

1.62Z-score

OE missense 0.82 (0.76–0.88)

496 obs / 608.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.04 (0.02–0.14)

0≤0.351.4

Missense OE0.82 (0.76–0.88)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 2 / 46.1Missense obs/exp: 496 / 608.4Syn Z: -1.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMECOM-related radioulnar synostosis with amegakaryocytic thrombocytopeniaGOFAD

0.2299th %ile

GOF

0.1799th %ile

LOF

0.89top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.14

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFWe observed a suppression of relative luciferase activity (RLA) in cells transfected with wild-type EVI1 compared with cells transfected with empty vector after treatment with 10% serum, whereas EVI1 mutants displayed enhanced suppressionthat is, a gain-of-function effect (Figure 3B).PMID:26581901

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.