Genetic Variant ENST00000514819.7:c.860C>A (chr19-19145983-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000514819.7(BORCS8-MEF2B):c.860C>A(p.Ala287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000778 in 1,285,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A287V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

BORCS8-MEF2B
ENST00000514819.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.805

Publications

0 publications found

Variant links:

Genes affected

BORCS8-MEF2B (HGNC:39979): (BORCS8-MEF2B readthrough) This gene represents numerous read-through transcripts that span GeneID:729991 and 100271849. Many read-through transcripts are predicted to be nonsense-mediated decay (NMD) candidates, and are thought to be non-coding. Some transcripts are predicted to be capable of translation reinitiation at a downstream AUG, resulting in expression of at least one isoform of myocyte enhancer factor 2B (MEF2B) from this read-through locus. At least one additional MEF2B variant and isoform can be expressed from a downstream promoter, and is annotated on GeneID:100271849. [provided by RefSeq, Oct 2010]

BORCS8-MEF2B links:

MEF2B (HGNC:6995): (myocyte enhancer factor 2B) The product of this gene is a member of the MADS/MEF2 family of DNA binding proteins. The protein is thought to regulate gene expression, including expression of the smooth muscle myosin heavy chain gene. This region undergoes considerable alternative splicing, with transcripts supporting two non-overlapping loci (GeneID 729991 and 100271849) as well as numerous read-through transcripts that span both loci (annotated as GeneID 4207). Several isoforms of this protein are expressed from either this locus or from some of the read-through transcripts annotated on GeneID 4207. [provided by RefSeq, Jan 2014]

MEF2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047275662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2B	NM_001145785.2 link	c.921C>A	p.Arg307Arg	synonymous_variant	Exon 9 of 9	ENST00000424583.7	NP_001139257.1	Q02080-2A0A024R7K5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BORCS8-MEF2B	ENST00000514819.7 link	c.860C>A	p.Ala287Glu	missense_variant	Exon 9 of 9	5		ENSP00000454967.3		H3BNR1
MEF2B	ENST00000424583.7 link	c.921C>A	p.Arg307Arg	synonymous_variant	Exon 9 of 9	5	NM_001145785.2	ENSP00000402154.2		Q02080-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.78e-7

AC:

AN:

1285182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

624606

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26016

American (AMR)

AF:

0.00

AC:

AN:

17868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18300

East Asian (EAS)

AF:

0.00

AC:

AN:

31746

South Asian (SAS)

AF:

0.00

AC:

AN:

62438

European-Finnish (FIN)

AF:

0.0000237

AC:

AN:

42278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1029966

Other (OTH)

AF:

0.00

AC:

AN:

52828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Benign

0.99

(source)

DANN

Benign

0.92

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.24

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.66

PhyloP100

-0.81

PROVEAN

Benign

-0.22

N;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

1.0

T;T

Vest4

0.057

MutPred

0.19

Gain of solvent accessibility (P = 0.0456);.;

MVP

0.081

MPC

0.43

ClinPred

0.065

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.11

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over