chr15-99712504-CCAGCAG-C

Variant names:

• chr15-99712504-CCAGCAG-C
• rs3138597
• NM_001319206.4:c.1280_1285delAGCAGC

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001319206.4(MEF2A):​c.1280_1285delAGCAGC​(p.Gln427_Gln428del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.314 in 1,520,352 control chromosomes in the GnomAD database, including 55,836 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (6336 hom., cov: 0)
  • Exomes 𝑓: 0.32 (49500 hom.)
• Consequence: MEF2A NM_001319206.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 6.55
• Publications: 9 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001319206.4
• BP6: Variant 15-99712504-CCAGCAG-C is Benign according to our data. Variant chr15-99712504-CCAGCAG-C is described in ClinVar as Benign. ClinVar VariationId is 403080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2A	NM_001319206.4	c.1280_1285delAGCAGC	p.Gln427_Gln428del	disruptive_inframe_deletion	Exon 12 of 12	ENST00000557942.6	NP_001306135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2A	ENST00000557942.6	c.1280_1285delAGCAGC	p.Gln427_Gln428del	disruptive_inframe_deletion	Exon 12 of 12	5	NM_001319206.4	ENSP00000453095.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39321 AN: 150108 Hom.: 6332 Cov.: 0

Gnomad AFR AF: 0.0663

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.324 AC: 39230 AN: 121148 AF XY: 0.334

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.320 AC: 438038 AN: 1370124 Hom.: 49500 AF XY: 0.322 AC XY: 217168 AN XY: 675480

African (AFR) AF: 0.0550 AC: 1709 AN: 31058

American (AMR) AF: 0.240 AC: 8381 AN: 34874

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 8365 AN: 24620

East Asian (EAS) AF: 0.314 AC: 10860 AN: 34608

South Asian (SAS) AF: 0.366 AC: 28326 AN: 77312

European-Finnish (FIN) AF: 0.353 AC: 16868 AN: 47752

Middle Eastern (MID) AF: 0.268 AC: 1506 AN: 5628

European-Non Finnish (NFE) AF: 0.326 AC: 344980 AN: 1057470

Other (OTH) AF: 0.300 AC: 17043 AN: 56802

GnomAD4 genome AF: 0.262 AC: 39321 AN: 150228 Hom.: 6336 Cov.: 0 AF XY: 0.264 AC XY: 19376 AN XY: 73292

African (AFR) AF: 0.0662 AC: 2706 AN: 40906

American (AMR) AF: 0.224 AC: 3388 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1281 AN: 3452

East Asian (EAS) AF: 0.335 AC: 1698 AN: 5062

South Asian (SAS) AF: 0.407 AC: 1913 AN: 4698

European-Finnish (FIN) AF: 0.390 AC: 3996 AN: 10238

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23300 AN: 67470

Other (OTH) AF: 0.251 AC: 520 AN: 2068

Alfa AF: 0.245 Hom.: 638

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

MEF2A-related disorder Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5
Mutation Taster		=193/7	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3138597; hg19: chr15-100252709; COSMIC: COSV57531553; COSMIC: COSV57531553;