3-169383111-G-A

Variant names:

• chr3-169383111-G-A
• rs448378
• NM_004991.4:c.38-1587C>T

Variant summary

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

The NM_004991.4(MECOM):​c.38-1587C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 151,756 control chromosomes in the GnomAD database, including 22,034 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 0.53 (22034 hom., cov: 30)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• Publications: 47 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 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.38-1587C>T		intron	N/A	NP_004982.2
	MECOM	NM_001366466.2		c.38-1587C>T		intron	N/A	NP_001353395.1
	MECOM	NM_001205194.2		c.-189-239279C>T		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.38-1587C>T		intron	N/A	ENSP00000498411.1
	MECOM	ENST00000485957.1	TSL:1	n.284-1587C>T		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.38-1587C>T		intron	N/A	ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80886 AN: 151638 Hom.: 22006 Cov.: 30

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.534 AC: 80962 AN: 151756 Hom.: 22034 Cov.: 30 AF XY: 0.537 AC XY: 39860 AN XY: 74172

African (AFR) AF: 0.490 AC: 20268 AN: 41340

American (AMR) AF: 0.615 AC: 9385 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1374 AN: 3468

East Asian (EAS) AF: 0.869 AC: 4477 AN: 5150

South Asian (SAS) AF: 0.493 AC: 2371 AN: 4806

European-Finnish (FIN) AF: 0.572 AC: 6012 AN: 10514

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.523 AC: 35515 AN: 67912

Other (OTH) AF: 0.535 AC: 1128 AN: 2108

Alfa AF: 0.532 Hom.: 74895

Bravo AF: 0.538

Asia WGS AF: 0.656 AC: 2279 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.48
PhyloP100		-0.031
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: rs448378; hg19: chr3-169100899;