rs9883650

Variant names:

• chr3-169362397-T-G
• rs9883650
• NM_004991.4:c.375+18790A>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.375+18790A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 151,872 control chromosomes in the GnomAD database, including 949 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 0.10 (949 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.960
• Publications: 7 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=-0.57).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 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.375+18790A>C		intron	N/A	NP_004982.2
	MECOM	NM_001366466.2		c.375+18790A>C		intron	N/A	NP_001353395.1
	MECOM	NM_001205194.2		c.-189-218565A>C		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.375+18790A>C		intron	N/A	ENSP00000498411.1
	MECOM	ENST00000485957.1	TSL:1	n.621+18790A>C		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.375+18790A>C		intron	N/A	ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15201 AN: 151754 Hom.: 946 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0953

Gnomad ASJ AF: 0.0364

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.100 AC: 15232 AN: 151872 Hom.: 949 Cov.: 32 AF XY: 0.0985 AC XY: 7313 AN XY: 74230

African (AFR) AF: 0.158 AC: 6551 AN: 41436

American (AMR) AF: 0.0955 AC: 1455 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 126 AN: 3466

East Asian (EAS) AF: 0.222 AC: 1135 AN: 5114

South Asian (SAS) AF: 0.0404 AC: 195 AN: 4824

European-Finnish (FIN) AF: 0.0464 AC: 493 AN: 10620

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0740 AC: 5025 AN: 67866

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.0846 Hom.: 2755

Bravo AF: 0.109

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.73
PhyloP100		0.96
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: rs9883650; hg19: chr3-169080185;