Genetic Variant BORCS8-MEF2B:p.Pro318His (chr19-19145890-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000514819.7(BORCS8-MEF2B):c.953C>A(p.Pro318His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,312,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P318L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

BORCS8-MEF2B
ENST00000514819.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.637

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10031912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2B	NM_001145785.2 link	c.1014C>A	p.Pro338Pro	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.953C>A	p.Pro318His	missense_variant	Exon 9 of 9	5		ENSP00000454967.3		H3BNR1
MEF2B	ENST00000424583.7 link	c.1014C>A	p.Pro338Pro	synonymous_variant	Exon 9 of 9	5	NM_001145785.2	ENSP00000402154.2		Q02080-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1312380

Hom.:

Cov.:

AF XY:

0.00000157

AC XY:

AN XY:

638498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28220

American (AMR)

AF:

0.00

AC:

AN:

22182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19554

East Asian (EAS)

AF:

0.00

AC:

AN:

34280

South Asian (SAS)

AF:

0.00

AC:

AN:

66552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

9.63e-7

AC:

AN:

1038498

Other (OTH)

AF:

0.00

AC:

AN:

54046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

0.097

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

4.3

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.21

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.49

PhyloP100

-0.64

PROVEAN

Benign

-0.59

N;.

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.028

D;D

Vest4

0.15

MutPred

0.078

Loss of glycosylation at P301 (P = 0.094);.;

MVP

0.40

MPC

0.43

ClinPred

0.35

GERP RS

0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

gMVP

0.065

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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19-19145890-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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