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

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]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

41 unique Pathogenic / Likely Pathogenic· 1073 VUS of 1746 total submissions

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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 OE?0.04 (0.02–0.14)

0≤0.351.4

Missense OE?0.82 (0.76–0.88)

0≤0.61.4

Synonymous OE?1.11

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

This gene — mechanism propensity

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 · 39% of P/LP variants are LoF · 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).1

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

References

1.PMID 26581901 ↗

ClinVar Variant Classifications

1746 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic23

VUS1073

Likely Benign569

Benign18

Conflicting22

Pathogenic

Likely Pathogenic

1073

VUS

569

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	8	0	0	18
Likely Pathogenic	6	12	5	0	23
VUS	5	1,054	13	1	1,073
Likely Benign	1	15	51	502	569
Benign	0	3	10	5	18
Conflicting	—				22
Total	22	1,092	79	508	1,723

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap MECOM — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →