chr3-169084945-C-T

Variant names:

• chr3-169084945-C-T
• rs750090830
• NM_004991.4:c.3684G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004991.4(MECOM):​c.3684G>A​(p.Ala1228Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MECOM NM_004991.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.25
• Publications: 1 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-169084945-C-T is Benign according to our data. Variant chr3-169084945-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3394384.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.25 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 17 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.3684G>A	p.Ala1228Ala	synonymous	Exon 17 of 17	NP_004982.2	Q03112-3
	MECOM	NM_001366466.2		c.3657G>A	p.Ala1219Ala	synonymous	Exon 16 of 16	NP_001353395.1	Q03112-7
	MECOM	NM_001105077.4		c.3315G>A	p.Ala1105Ala	synonymous	Exon 17 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.3684G>A	p.Ala1228Ala	synonymous	Exon 17 of 17	ENSP00000498411.1	Q03112-3
	MECOM	ENST00000264674.7	TSL:1	c.3315G>A	p.Ala1105Ala	synonymous	Exon 17 of 17	ENSP00000264674.3	Q03112-4
	MECOM	ENST00000433243.6	TSL:1	c.3123G>A	p.Ala1041Ala	synonymous	Exon 17 of 17	ENSP00000394302.2	A0A0C3SFZ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251310 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.49
PhyloP100		-2.3

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: rs750090830; hg19: chr3-168802733; COSMIC: COSV52970477;