15-99712390-T-C

Position:

• chr15-99712390-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001319206.4(MEF2A):​c.1137T>C​(p.Val379=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,530,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (0 hom.)
• Consequence: MEF2A NM_001319206.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002783
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.952

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

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-99712390-T-C is Benign according to our data. Variant chr15-99712390-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3043823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.952 with no splicing effect.
• BS2: High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEF2A	NM_001319206.4	c.1137T>C	p.Val379=	splice_region_variant, synonymous_variant	12/12	ENST00000557942.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEF2A	ENST00000557942.6	c.1137T>C	p.Val379=	splice_region_variant, synonymous_variant	12/12	5	NM_001319206.4

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000647 AC: 95 AN: 146734 Hom.: 0 AF XY: 0.000692 AC XY: 53 AN XY: 76566

Gnomad AFR exome AF: 0.000243

Gnomad AMR exome AF: 0.000247

Gnomad ASJ exome AF: 0.000936

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000977

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000912 AC: 1257 AN: 1378350 Hom.: 0 Cov.: 30 AF XY: 0.000900 AC XY: 608 AN XY: 675840

Gnomad4 AFR exome AF: 0.000192

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.000457

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000651

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000559

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74462

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.000733

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

MEF2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.76
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.010
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

Publications

LitVar

Other links and lift over

dbSNP: rs199613639; hg19: chr15-100252595;