rs3851378

Variant names:

• chr3-169120161-C-A
• rs3851378
• NM_004991.4:c.1132+895G>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.1132+895G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 152,238 control chromosomes in the GnomAD database, including 59,784 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 0.89 (59784 hom., cov: 32)
• Consequence: MECOM NM_004991.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 6 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECOM	NM_004991.4	c.1132+895G>T		intron_variant	Intron 7 of 16	ENST00000651503.2	NP_004982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECOM	ENST00000651503.2	c.1132+895G>T		intron_variant	Intron 7 of 16		NM_004991.4	ENSP00000498411.1

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134665 AN: 152120 Hom.: 59734 Cov.: 32

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.883

Gnomad AMR AF: 0.901

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.951

Gnomad MID AF: 0.857

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.891

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

GnomAD4 genome AF: 0.885 AC: 134768 AN: 152238 Hom.: 59784 Cov.: 32 AF XY: 0.885 AC XY: 65883 AN XY: 74444

African (AFR) AF: 0.865 AC: 35944 AN: 41538

American (AMR) AF: 0.901 AC: 13781 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3089 AN: 3472

East Asian (EAS) AF: 0.836 AC: 4325 AN: 5174

South Asian (SAS) AF: 0.757 AC: 3644 AN: 4812

European-Finnish (FIN) AF: 0.951 AC: 10086 AN: 10606

Middle Eastern (MID) AF: 0.860 AC: 251 AN: 292

European-Non Finnish (NFE) AF: 0.896 AC: 60970 AN: 68030

Other (OTH) AF: 0.888 AC: 1873 AN: 2110

Alfa AF: 0.892 Hom.: 274046

Bravo AF: 0.885

Asia WGS AF: 0.809 AC: 2812 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs3851378; hg19: chr3-168837949;