chr15-99645655-G-C

Variant names:

• chr15-99645655-G-C
• rs754843909
• NM_001319206.4:c.149G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001319206.4(MEF2A):​c.149G>C​(p.Ser50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MEF2A NM_001319206.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2A	NM_001319206.4	c.149G>C	p.Ser50Thr	missense_variant	Exon 4 of 12	ENST00000557942.6	NP_001306135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2A	ENST00000557942.6	c.149G>C	p.Ser50Thr	missense_variant	Exon 4 of 12	5	NM_001319206.4	ENSP00000453095.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249118 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461348 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149G>C (p.S50T) alteration is located in exon 4 (coding exon 2) of the MEF2A gene. This alteration results from a G to C substitution at nucleotide position 149, causing the serine (S) at amino acid position 50 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;T;T;.;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.93	.;L;L;L;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;N;N;N;N;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.014	D;D;D;D;D;D
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.30, 0.81, 0.88	.;B;P;P;P;.
Vest4		0.53, 0.53, 0.54, 0.53
MutPred		0.71		Loss of catalytic residue at S50 (P = 0.0573);Loss of catalytic residue at S50 (P = 0.0573);Loss of catalytic residue at S50 (P = 0.0573);Loss of catalytic residue at S50 (P = 0.0573);Loss of catalytic residue at S50 (P = 0.0573);Loss of catalytic residue at S50 (P = 0.0573);
MVP		0.52
MPC		1.5
ClinPred		0.92	D
GERP RS		5.2
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754843909; hg19: chr15-100185860;