rs12634933

Variant names:

• chr3-169312191-A-G
• rs12634933
• NM_004991.4:c.375+68996T>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+68996T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 152,226 control chromosomes in the GnomAD database, including 731 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 0.084 (731 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91
• Publications: 5 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECOM	NM_004991.4	c.375+68996T>C		intron_variant	Intron 2 of 16	ENST00000651503.2	NP_004982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECOM	ENST00000651503.2	c.375+68996T>C		intron_variant	Intron 2 of 16		NM_004991.4	ENSP00000498411.1
MECOM	ENST00000485957.1	n.621+68996T>C		intron_variant	Intron 2 of 2	1
MECOM	ENST00000494292.6	c.375+68996T>C		intron_variant	Intron 2 of 15	5		ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.0838 AC: 12750 AN: 152104 Hom.: 732 Cov.: 32

Gnomad AFR AF: 0.0870

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.0749

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.0803

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0935

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

GnomAD4 genome AF: 0.0838 AC: 12750 AN: 152226 Hom.: 731 Cov.: 32 AF XY: 0.0848 AC XY: 6313 AN XY: 74438

African (AFR) AF: 0.0871 AC: 3619 AN: 41542

American (AMR) AF: 0.0572 AC: 874 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0749 AC: 260 AN: 3470

East Asian (EAS) AF: 0.333 AC: 1722 AN: 5166

South Asian (SAS) AF: 0.0793 AC: 382 AN: 4818

European-Finnish (FIN) AF: 0.0587 AC: 623 AN: 10616

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0732 AC: 4982 AN: 68014

Other (OTH) AF: 0.0929 AC: 196 AN: 2110

Alfa AF: 0.0794 Hom.: 64

Bravo AF: 0.0848

Asia WGS AF: 0.184 AC: 637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.034
DANN	Benign	0.30
PhyloP100		-1.9
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: rs12634933; hg19: chr3-169029979;