3-169422102-T-C

Variant names:

• chr3-169422102-T-C
• rs1918969
• NM_004991.4:c.38-40578A>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.38-40578A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,924 control chromosomes in the GnomAD database, including 16,135 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 0.45 (16135 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.654
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 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.38-40578A>G		intron	N/A	NP_004982.2	Q03112-3
	MECOM	NM_001366466.2		c.38-40578A>G		intron	N/A	NP_001353395.1	Q03112-7
	MECOM	NM_001205194.2		c.-190+241234A>G		intron	N/A	NP_001192123.1	Q03112-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	ENST00000651503.2	MANE Select	c.38-40578A>G		intron	N/A	ENSP00000498411.1	Q03112-3
	MECOM	ENST00000485957.1	TSL:1	n.284-40578A>G		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.38-40578A>G		intron	N/A	ENSP00000417899.1	Q03112-7

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68797 AN: 151806 Hom.: 16119 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.462

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

GnomAD4 genome AF: 0.453 AC: 68851 AN: 151924 Hom.: 16135 Cov.: 32 AF XY: 0.457 AC XY: 33895 AN XY: 74236

African (AFR) AF: 0.393 AC: 16281 AN: 41472

American (AMR) AF: 0.556 AC: 8467 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3468

East Asian (EAS) AF: 0.769 AC: 3973 AN: 5166

South Asian (SAS) AF: 0.421 AC: 2029 AN: 4818

European-Finnish (FIN) AF: 0.461 AC: 4863 AN: 10538

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30787 AN: 67910

Other (OTH) AF: 0.461 AC: 972 AN: 2110

Alfa AF: 0.447 Hom.: 38950

Bravo AF: 0.460

Asia WGS AF: 0.547 AC: 1895 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.48
DANN	Benign	0.58
PhyloP100		-0.65
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: rs1918969; hg19: chr3-169139890;