rs864309724

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_004991.4(MECOM):c.2812C>T(p.Arg938Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R938Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MECOM
NM_004991.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.64

Publications

7 publications found

Variant links:

Genes affected

MECOM (HGNC:3498): (MDS1 and EVI1 complex locus) 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]

MECOM Gene-Disease associations (from GenCC):

MECOM-associated syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
radioulnar synostosis with amegakaryocytic thrombocytopenia 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MECOM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_004991.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-169100921-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2506775.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

PP5

Variant 3-169100922-G-A is Pathogenic according to our data. Variant chr3-169100922-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECOM	NM_004991.4 link	c.2812C>T	p.Arg938Trp	missense_variant	Exon 12 of 17	ENST00000651503.2	NP_004982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECOM	ENST00000651503.2 link	c.2812C>T	p.Arg938Trp	missense_variant	Exon 12 of 17		NM_004991.4	ENSP00000498411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724312

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

85252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108490

Other (OTH)

AF:

0.00

AC:

AN:

60088

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2

Pathogenic:2

Dec 03, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 18, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:2

Jan 27, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29519864, 20091385, 26581901, 29540340, 29097497, 29200407, 32098966, Pronama2021[Review], 35219593, 35470277, 36515795) -

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 750 of the MECOM protein (p.Arg750Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of radioulnar synostosis with amegakaryocytic thrombocytopenia (PMID: 26581901, 29146883, 29200407, 29519864). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 218953). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MECOM function (PMID: 26581901, 35219593). For these reasons, this variant has been classified as Pathogenic. -

MECOM-related disorder

Pathogenic:1

May 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MECOM c.2248C>T variant is predicted to result in the amino acid substitution p.Arg750Trp. This variant has been reported as a recurrent de novo variant in individuals with radioulnar synostosis with amegakaryocytic thrombocytopenia-2 (Niihori et al. 2015. PubMed ID: 26581901; Germeshausen et al. 2018. PubMed ID: 29540340; Lord et al. 2018. PubMed ID: 29200407; Walne et al. 2018. PubMed ID: 29519864). This variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret c.2248C>T (p.Arg750Trp) as pathogenic. -

MECOM-associated syndrome

Pathogenic:1

Jul 18, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The p.Arg938Trp (also known as p.Arg750Trp) variant in MECOM has been reported in at least 7 individuals with MECOM-associated syndrome (PMID: 29540340, 29200407, 295198642, 26581901, 29519864), and was absent from large population studies. This variant was found to be de novo in at least 5 individuals with and without confirmed paternity and maternity (PMID: 29540340, 29200407, 295198642). This variant has also been reported in ClinVar (VCV000218953.7) and has been interpreted as pathogenic by Baylor Genetics, GeneDx, Labcorp Genetics, OMIM and PreventionGenetics. In vitro functional studies provide some evidence that the p.Arg938Trp variant may slightly impact protein function (PMID: 26581901). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Arg938Trp variant is located in a region of MECOM that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 35219593). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant MECOM-associated syndrome. ACMG/AMP Criteria applied: PS2_moderate, PM1_supporting, PM2_supporting, PS3_supporting, PS4_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

.;.;.;T;.;.;.;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;.;D;.;D;D

M_CAP

Uncertain

0.085

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

PhyloP100

5.6

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-7.2

D;.;D;D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;.;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.;.

Vest4

0.85

MutPred

0.63

.;.;.;.;Loss of disorder (P = 0.0024);.;.;.;

MVP

0.67

MPC

3.1

ClinPred

0.99

GERP RS

4.7

Varity_R

0.81

gMVP

0.84

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over