Genetic Variant MEF2A:p.Gln423_Gln428del (chr15-99712504-CCAGCAGCAGCAGCAGCAG-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001319206.4(MEF2A):c.1268_1285delAGCAGCAGCAGCAGCAGC(p.Gln423_Gln428del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00198 in 1,531,506 control chromosomes in the GnomAD database, including 20 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0018 ( 17 hom. )

Consequence

MEF2A
NM_001319206.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.73

Publications

9 publications found

Variant links:

Genes affected

MEF2A (HGNC:6993): (myocyte enhancer factor 2A) The protein encoded by this gene is a DNA-binding transcription factor that activates many muscle-specific, growth factor-induced, and stress-induced genes. The encoded protein can act as a homodimer or as a heterodimer and is involved in several cellular processes, including muscle development, neuronal differentiation, cell growth control, and apoptosis. Defects in this gene could be a cause of autosomal dominant coronary artery disease 1 with myocardial infarction (ADCAD1). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

MEF2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001319206.4

BS2

High AC in GnomAd4 at 516 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2A	NM_001319206.4 link	c.1268_1285delAGCAGCAGCAGCAGCAGC	p.Gln423_Gln428del	disruptive_inframe_deletion	Exon 12 of 12	ENST00000557942.6	NP_001306135.1	Q02078-2A0A0S2Z4N0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2A	ENST00000557942.6 link	c.1268_1285delAGCAGCAGCAGCAGCAGC	p.Gln423_Gln428del	disruptive_inframe_deletion	Exon 12 of 12	5	NM_001319206.4	ENSP00000453095.1		Q02078-2

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

516

AN:

150286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00809

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00106

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00197

Gnomad SAS

AF:

0.0115

Gnomad FIN

AF:

0.000389

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000859

Gnomad OTH

AF:

0.00342

GnomAD4 exome

AF:

0.00182

AC:

2509

AN:

1381102

Hom.:

AF XY:

0.00205

AC XY:

1398

AN XY:

681098

show subpopulations

African (AFR)

AF:

0.00739

AC:

232

AN:

31384

American (AMR)

AF:

0.00124

AC:

AN:

35366

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

271

AN:

24826

East Asian (EAS)

AF:

0.00436

AC:

153

AN:

35112

South Asian (SAS)

AF:

0.00925

AC:

722

AN:

78078

European-Finnish (FIN)

AF:

0.000292

AC:

AN:

47944

Middle Eastern (MID)

AF:

0.00336

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.000868

AC:

925

AN:

1065408

Other (OTH)

AF:

0.00225

AC:

129

AN:

57332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00343

AC:

516

AN:

150404

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

244

AN XY:

73376

show subpopulations

African (AFR)

AF:

0.00809

AC:

331

AN:

40928

American (AMR)

AF:

0.00106

AC:

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3464

East Asian (EAS)

AF:

0.00197

AC:

AN:

5072

South Asian (SAS)

AF:

0.0113

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.000389

AC:

AN:

10274

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000859

AC:

AN:

67536

Other (OTH)

AF:

0.00338

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000523

Hom.:

638

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Coronary artery disease, autosomal dominant, 1

Uncertain:1

Nov 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.7

Mutation Taster

=171/29

polymorphism

(source)

Splicing

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

Publications

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15-99712504-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over