chr3-169253443-A-G

Variant names:

• chr3-169253443-A-G
• rs784288
• NM_004991.4:c.376-109611T>C

Variant summary

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

The NM_004991.4(MECOM):​c.376-109611T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 150,508 control chromosomes in the GnomAD database, including 18,921 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 0.49 (18921 hom., cov: 29)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 21 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.689 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	NM_004991.4	MANE Select	c.376-109611T>C		intron	N/A	NP_004982.2
	MECOM	NM_001366466.2		c.376-109611T>C		intron	N/A	NP_001353395.1
	MECOM	NM_001205194.2		c.-189-109611T>C		intron	N/A	NP_001192123.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	ENST00000651503.2	MANE Select	c.376-109611T>C		intron	N/A	ENSP00000498411.1
	MECOM	ENST00000485957.1	TSL:1	n.622-103688T>C		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.376-109611T>C		intron	N/A	ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 73692 AN: 150422 Hom.: 18909 Cov.: 29

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.436

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

GnomAD4 genome AF: 0.490 AC: 73734 AN: 150508 Hom.: 18921 Cov.: 29 AF XY: 0.494 AC XY: 36295 AN XY: 73428

African (AFR) AF: 0.621 AC: 25456 AN: 41008

American (AMR) AF: 0.484 AC: 7324 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1197 AN: 3462

East Asian (EAS) AF: 0.708 AC: 3617 AN: 5106

South Asian (SAS) AF: 0.562 AC: 2681 AN: 4774

European-Finnish (FIN) AF: 0.411 AC: 4137 AN: 10066

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 27941 AN: 67690

Other (OTH) AF: 0.439 AC: 913 AN: 2082

Alfa AF: 0.451 Hom.: 27927

Bravo AF: 0.501

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.40
PhyloP100		1.0
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: rs784288; hg19: chr3-168971231;