chr3-169198452-T-C

Variant names:

• chr3-169198452-T-C
• rs9864370
• NM_004991.4:c.376-54620A>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.376-54620A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.076 in 152,114 control chromosomes in the GnomAD database, including 514 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 0.076 (514 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 9 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECOM	NM_004991.4	c.376-54620A>G		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.376-54620A>G		intron_variant	Intron 2 of 16		NM_004991.4	ENSP00000498411.1
MECOM	ENST00000485957.1	n.622-48697A>G		intron_variant	Intron 2 of 2	1
MECOM	ENST00000494292.6	c.376-54620A>G		intron_variant	Intron 2 of 15	5		ENSP00000417899.1
MECOM	ENST00000481315.1	c.-189-54620A>G		intron_variant	Intron 1 of 3	5		ENSP00000418046.1

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11551 AN: 151996 Hom.: 510 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0614

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

GnomAD4 genome AF: 0.0760 AC: 11566 AN: 152114 Hom.: 514 Cov.: 32 AF XY: 0.0814 AC XY: 6050 AN XY: 74370

African (AFR) AF: 0.0578 AC: 2402 AN: 41540

American (AMR) AF: 0.0697 AC: 1064 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 157 AN: 3468

East Asian (EAS) AF: 0.120 AC: 620 AN: 5158

South Asian (SAS) AF: 0.202 AC: 974 AN: 4820

European-Finnish (FIN) AF: 0.113 AC: 1196 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0732 AC: 4974 AN: 67948

Other (OTH) AF: 0.0665 AC: 140 AN: 2106

Alfa AF: 0.0690 Hom.: 1023

Bravo AF: 0.0694

Asia WGS AF: 0.156 AC: 545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.4
DANN	Benign	0.88
PhyloP100		-1.1
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: rs9864370; hg19: chr3-168916240;