3-169503316-G-C

Variant names:

• chr3-169503316-G-C
• rs12495069
• NM_004991.4:c.38-121792C>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.38-121792C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 151,844 control chromosomes in the GnomAD database, including 10,400 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 0.35 (10400 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 4 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

ENSG00000302206 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.531 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.38-121792C>G		intron	N/A	NP_004982.2
	MECOM	NM_001366466.2		c.38-121792C>G		intron	N/A	NP_001353395.1
	MECOM	NM_001205194.2		c.-190+160020C>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.38-121792C>G		intron	N/A	ENSP00000498411.1
	MECOM	ENST00000485957.1	TSL:1	n.284-121792C>G		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.38-121792C>G		intron	N/A	ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53065 AN: 151726 Hom.: 10399 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.350 AC: 53091 AN: 151844 Hom.: 10400 Cov.: 32 AF XY: 0.342 AC XY: 25349 AN XY: 74222

African (AFR) AF: 0.537 AC: 22237 AN: 41424

American (AMR) AF: 0.265 AC: 4048 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 815 AN: 3462

East Asian (EAS) AF: 0.173 AC: 894 AN: 5174

South Asian (SAS) AF: 0.150 AC: 719 AN: 4806

European-Finnish (FIN) AF: 0.293 AC: 3084 AN: 10520

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20239 AN: 67882

Other (OTH) AF: 0.326 AC: 688 AN: 2108

Alfa AF: 0.328 Hom.: 1090

Bravo AF: 0.360

Asia WGS AF: 0.179 AC: 626 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.61
DANN	Benign	0.36
PhyloP100		-0.099
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: rs12495069; hg19: chr3-169221104;