3-169115672-G-T

Variant names:

• chr3-169115672-G-T
• rs1553838272
• NM_004991.4:c.2200C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004991.4(MECOM):​c.2200C>A​(p.Gln734Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q734P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MECOM NM_004991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59
• Publications: 0 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), G2P, Ambry Genetics
• radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09119806).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	NM_004991.4	MANE Select	c.2200C>A	p.Gln734Lys	missense	Exon 8 of 17	NP_004982.2	Q03112-3
	MECOM	NM_001366466.2		c.2200C>A	p.Gln734Lys	missense	Exon 8 of 16	NP_001353395.1	Q03112-7
	MECOM	NM_001105077.4		c.1831C>A	p.Gln611Lys	missense	Exon 8 of 17	NP_001098547.3	Q03112-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECOM	ENST00000651503.2	MANE Select	c.2200C>A	p.Gln734Lys	missense	Exon 8 of 17	ENSP00000498411.1	Q03112-3
	MECOM	ENST00000264674.7	TSL:1	c.1831C>A	p.Gln611Lys	missense	Exon 8 of 17	ENSP00000264674.3	Q03112-4
	MECOM	ENST00000433243.6	TSL:1	c.1639C>A	p.Gln547Lys	missense	Exon 8 of 17	ENSP00000394302.2	A0A0C3SFZ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.70
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.97	T
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.12
Sift	Benign	0.46	T
Sift4G	Benign	0.91	T
Polyphen		0.15	B
Vest4		0.27
MutPred		0.27		Gain of methylation at Q734 (P = 0.003)
MVP		0.043
MPC		0.43
ClinPred		0.22	T
GERP RS		5.0
Varity_R		0.090
gMVP		0.13
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553838272; hg19: chr3-168833460; COSMIC: COSV52960825;