rs864309724

Variant names:

• chr3-169100922-G-A
• rs864309724
• NM_004991.4:c.2812C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MECOM NM_004991.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218953.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456170 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 Pathogenic:2 Uncertain:1

Dec 03, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg815Trp variant in MECOM was identified by our study in one individual with radioulnar synostosis with amegakaryocytic thrombocytopenia. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg815Trp variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015). -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;.;T;.;.;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;.;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.97	D
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	D
GERP RS		4.7
Varity_R		0.81
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs864309724; hg19: chr3-168818710;