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…

Primary Disease Associations & Inheritance

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2MIM #616738

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · MECOM-associated syndrome · AD · ClinGen 2021

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.14

LOEUF· LoF intol.

GOF*

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in MECOM?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 45

1,420 rare PASS variants

Rare truncating (LoF)

1 in 3,700

46 rare PASS variants

Rare synonymous (reference)

1 in 60

561 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MECOM. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 53	1 in 4,800
South Asian	~43k	1 in 38	1 in 1,700
Remaining (unassigned)	~30k	1 in 37	≈ 1 in 9,700
European (Finnish)	~27k	1 in 170	≈ 1 in 27,000
Admixed American	~22k	1 in 59	≈ 1 in 7,600
African / African American	~21k	1 in 43	1 in 3,800
East Asian	~20k	1 in 51	1 in 790
Ashkenazi Jewish	~13k	1 in 140	none seen
Middle Eastern	~2,884	1 in 44	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 17 coding exons well covered in gnomAD exomes and genomes.? see exons ↓