3-169383098-T-C

Variant names:

• chr3-169383098-T-C
• rs419076
• NM_004991.4:c.38-1574A>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.38-1574A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 151,690 control chromosomes in the GnomAD database, including 22,021 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 (22021 hom., cov: 30)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.829
• Publications: 63 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECOM	NM_004991.4	c.38-1574A>G		intron_variant	Intron 1 of 16	ENST00000651503.2	NP_004982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECOM	ENST00000651503.2	c.38-1574A>G		intron_variant	Intron 1 of 16		NM_004991.4	ENSP00000498411.1
MECOM	ENST00000485957.1	n.284-1574A>G		intron_variant	Intron 1 of 2	1
MECOM	ENST00000494292.6	c.38-1574A>G		intron_variant	Intron 1 of 15	5		ENSP00000417899.1
MECOM	ENST00000486748.2	c.110-1574A>G		intron_variant	Intron 2 of 2	5		ENSP00000419537.1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80842 AN: 151572 Hom.: 21993 Cov.: 30

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.571

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: 0.533 AC: 80918 AN: 151690 Hom.: 22021 Cov.: 30 AF XY: 0.537 AC XY: 39831 AN XY: 74174

African (AFR) AF: 0.490 AC: 20243 AN: 41326

American (AMR) AF: 0.615 AC: 9377 AN: 15248

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

East Asian (EAS) AF: 0.871 AC: 4481 AN: 5144

South Asian (SAS) AF: 0.493 AC: 2368 AN: 4800

European-Finnish (FIN) AF: 0.571 AC: 6002 AN: 10504

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

European-Non Finnish (NFE) AF: 0.523 AC: 35514 AN: 67892

Other (OTH) AF: 0.536 AC: 1129 AN: 2108

Alfa AF: 0.529 Hom.: 64838

Bravo AF: 0.538

Asia WGS AF: 0.661 AC: 2294 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.33
PhyloP100		-0.83
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: rs419076; hg19: chr3-169100886;