Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

The NM_004991.4(MECOM):c.2830A>G(p.Thr944Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T944I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MECOM
NM_004991.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.02

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr3-169100903-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3900742.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

PP5

Variant 3-169100904-T-C is Pathogenic according to our data. Variant chr3-169100904-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 218951.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004991.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MECOM	NM_004991.4	MANE Select	c.2830A>G	p.Thr944Ala	missense	Exon 12 of 17	NP_004982.2
MECOM	NM_001366466.2		c.2803A>G	p.Thr935Ala	missense	Exon 11 of 16	NP_001353395.1
MECOM	NM_001105077.4		c.2461A>G	p.Thr821Ala	missense	Exon 12 of 17	NP_001098547.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MECOM	ENST00000651503.2	MANE Select	c.2830A>G	p.Thr944Ala	missense	Exon 12 of 17	ENSP00000498411.1
MECOM	ENST00000264674.7	TSL:1	c.2461A>G	p.Thr821Ala	missense	Exon 12 of 17	ENSP00000264674.3
MECOM	ENST00000433243.6	TSL:1	c.2269A>G	p.Thr757Ala	missense	Exon 12 of 17	ENSP00000394302.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.63

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.97

PhyloP100

8.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.84

MutPred

0.45

Loss of phosphorylation at T935 (P = 0.0564)

MVP

0.57

MPC

3.0

ClinPred

1.0

GERP RS

5.5

Varity_R

0.68

gMVP

0.73

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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rs864309722

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over