ENST00000514819.7:c.1094G>T

Variant names:

• chr19-19145749-C-A
• rs2060019224
• ENST00000514819.7:c.1094G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000514819.7(BORCS8-MEF2B):​c.1094G>T​(p.Arg365Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. R365T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BORCS8-MEF2B ENST00000514819.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.989
• Publications: 0 publications found

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]

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]

ACMG classification

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=0.16892931).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000514819.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2B	NM_001145785.2	MANE Select	c.*48G>T		3_prime_UTR	Exon 9 of 9	NP_001139257.1	Q02080-2
	MEF2B	NM_001367282.1		c.1043G>T	p.Arg348Met	missense	Exon 8 of 8	NP_001354211.1	Q02080-1
	BORCS8-MEF2B	NM_005919.4		c.1043G>T	p.Arg348Met	missense	Exon 10 of 10	NP_005910.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BORCS8-MEF2B	ENST00000514819.7	TSL:5	c.1094G>T	p.Arg365Met	missense	Exon 9 of 9	ENSP00000454967.3	H3BNR1
	MEF2B	ENST00000424583.7	TSL:5 MANE Select	c.*48G>T		3_prime_UTR	Exon 9 of 9	ENSP00000402154.2	Q02080-2
	MEF2B	ENST00000444486.7	TSL:2	c.1043G>T	p.Arg348Met	missense	Exon 10 of 10	ENSP00000390762.2	Q02080-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405022 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 693478

African (AFR) AF: 0.00 AC: 0 AN: 32346

American (AMR) AF: 0.00 AC: 0 AN: 35912

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36926

South Asian (SAS) AF: 0.00 AC: 0 AN: 79728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082820

Other (OTH) AF: 0.00 AC: 0 AN: 58256

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	5.5
DANN	Benign	0.87
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.55	T
PhyloP100		0.99
PROVEAN	Benign	0.34	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Vest4		0.28
MutPred		0.27		Loss of methylation at R348 (P = 0.0121)
MVP		0.30
MPC		0.41
ClinPred		0.14	T
GERP RS		1.1
gMVP		0.054
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2060019224; hg19: chr19-19256558;