rs6774494

Variant names:

• chr3-169364845-G-A
• rs6774494
• NM_004991.4:c.375+16342C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-169364845-G-A
• chr3-169364845-G-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.375+16342C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,750 control chromosomes in the GnomAD database, including 14,918 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 0.42 (14918 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.885
• Publications: 39 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=-0.52).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.591 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+16342C>T		intron	N/A	NP_004982.2
	MECOM	NM_001366466.2		c.375+16342C>T		intron	N/A	NP_001353395.1
	MECOM	NM_001205194.2		c.-189-221013C>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.375+16342C>T		intron	N/A	ENSP00000498411.1
	MECOM	ENST00000485957.1	TSL:1	n.621+16342C>T		intron	N/A
	MECOM	ENST00000494292.6	TSL:5	c.375+16342C>T		intron	N/A	ENSP00000417899.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63624 AN: 151632 Hom.: 14870 Cov.: 32

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.420 AC: 63735 AN: 151750 Hom.: 14918 Cov.: 32 AF XY: 0.422 AC XY: 31290 AN XY: 74138

African (AFR) AF: 0.598 AC: 24760 AN: 41430

American (AMR) AF: 0.509 AC: 7756 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 691 AN: 3468

East Asian (EAS) AF: 0.589 AC: 3005 AN: 5102

South Asian (SAS) AF: 0.268 AC: 1289 AN: 4818

European-Finnish (FIN) AF: 0.368 AC: 3883 AN: 10552

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21186 AN: 67844

Other (OTH) AF: 0.401 AC: 843 AN: 2104

Alfa AF: 0.350 Hom.: 48018

Bravo AF: 0.447

Asia WGS AF: 0.468 AC: 1624 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.9
DANN	Benign	0.50
PhyloP100		0.89
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: rs6774494; hg19: chr3-169082633; COSMIC: COSV72256703;