rs864309724

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.64
• Publications: 7 publications found

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), G2P, Ambry Genetics
• radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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_multiple_submitters_no_conflicts, 2 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	NM_004991.4	MANE Select	c.2812C>T	p.Arg938Trp	missense	Exon 12 of 17	NP_004982.2	Q03112-3
	MECOM	NM_001366466.2		c.2785C>T	p.Arg929Trp	missense	Exon 11 of 16	NP_001353395.1	Q03112-7
	MECOM	NM_001105077.4		c.2443C>T	p.Arg815Trp	missense	Exon 12 of 17	NP_001098547.3	Q03112-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	ENST00000651503.2	MANE Select	c.2812C>T	p.Arg938Trp	missense	Exon 12 of 17	ENSP00000498411.1	Q03112-3
	MECOM	ENST00000264674.7	TSL:1	c.2443C>T	p.Arg815Trp	missense	Exon 12 of 17	ENSP00000264674.3	Q03112-4
	MECOM	ENST00000433243.6	TSL:1	c.2251C>T	p.Arg751Trp	missense	Exon 12 of 17	ENSP00000394302.2	A0A0C3SFZ7

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

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108490

Other (OTH) AF: 0.00 AC: 0 AN: 60088

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	MECOM-associated syndrome (2)
2	-	-	not provided (2)
2	-	-	Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 (2)
1	-	-	MECOM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
PhyloP100		5.6
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864309724; hg19: chr3-168818710;