NM_004991.4:c.38-51320A>G

Variant names:

• chr3-169432844-T-C
• rs16853722
• NM_004991.4:c.38-51320A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004991.4(MECOM):​c.38-51320A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,214 control chromosomes in the GnomAD database, including 1,285 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1285 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.569
• Publications: 16 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), Ambry Genetics, G2P
• radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	NM_004991.4	MANE Select	c.38-51320A>G		intron	N/A	NP_004982.2
	MECOM	NM_001366466.2		c.38-51320A>G		intron	N/A	NP_001353395.1
	MECOM	NM_001205194.2		c.-190+230492A>G		intron	N/A	NP_001192123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	ENST00000651503.2	MANE Select	c.38-51320A>G		intron	N/A	ENSP00000498411.1
	MECOM	ENST00000485957.1	TSL:1	n.284-51320A>G		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.38-51320A>G		intron	N/A	ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17563 AN: 152096 Hom.: 1289 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 17551 AN: 152214 Hom.: 1285 Cov.: 32 AF XY: 0.121 AC XY: 9032 AN XY: 74404

African (AFR) AF: 0.0482 AC: 2005 AN: 41570

American (AMR) AF: 0.109 AC: 1667 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 244 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1513 AN: 5152

South Asian (SAS) AF: 0.160 AC: 771 AN: 4826

European-Finnish (FIN) AF: 0.235 AC: 2485 AN: 10576

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8482 AN: 68008

Other (OTH) AF: 0.104 AC: 220 AN: 2114

Alfa AF: 0.123 Hom.: 3446

Bravo AF: 0.106

Asia WGS AF: 0.201 AC: 697 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.63
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs16853722; hg19: chr3-169150632;