dbSNP rs121918529: MEF2A:p.Pro277Leu (chr15-99690400-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP5BP4BS2_Supporting

The NM_001319206.4(MEF2A):c.830C>T(p.Pro277Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,604,264 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

MEF2A
NM_001319206.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.57

Publications

33 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a mutagenesis_site Reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with A-278. (size 0) in uniprot entity MEF2A_HUMAN

PP5

Variant 15-99690400-C-T is Pathogenic according to our data. Variant chr15-99690400-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8949.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.21290135). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 101 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2A	NM_001319206.4 link	c.830C>T	p.Pro277Leu	missense_variant	Exon 8 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.830C>T	p.Pro277Leu	missense_variant	Exon 8 of 12	5	NM_001319206.4	ENSP00000453095.1		Q02078-2

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000606

AC:

147

AN:

242696

AF XY:

0.000661

show subpopulations

Gnomad AFR exome

AF:

0.000197

Gnomad AMR exome

AF:

0.000452

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000856

GnomAD4 exome

AF:

0.00100

AC:

1456

AN:

1451936

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

706

AN XY:

720686

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33202

American (AMR)

AF:

0.000433

AC:

AN:

43830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25770

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.000306

AC:

AN:

85002

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00123

AC:

1360

AN:

1105748

Other (OTH)

AF:

0.000768

AC:

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152328

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41578

American (AMR)

AF:

0.000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000696

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000526

AC:

ESP6500EA

AF:

0.000729

AC:

ExAC

AF:

0.000703

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Coronary artery disease/myocardial infarction

Pathogenic:1

Feb 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D;.;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.8

M;.;.;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D;T

Polyphen

0.97

D;.;D;D;.;D

Vest4

0.82

MVP

0.29

MPC

0.41

ClinPred

0.12

GERP RS

5.8

gMVP

0.58

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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rs121918529

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