19-19182640-C-T

Variant names:

• chr19-19182640-C-T
• rs566625799
• ENST00000514819.7:c.-46G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005919.4(BORCS8-MEF2B):​c.-173G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,551,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BORCS8-MEF2B NM_005919.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

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 (HGNC:37247): (BLOC-1 related complex subunit 8) Involved in heart development. Part of BORC complex. [provided by Alliance of Genome Resources, Apr 2022]

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17803869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BORCS8	NM_001145784.2	c.259G>A	p.Val87Met	missense_variant	Exon 4 of 6	ENST00000462790.8	NP_001139256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BORCS8-MEF2B	ENST00000514819.7	c.-46G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	5		ENSP00000454967.3
BORCS8	ENST00000462790.8	c.259G>A	p.Val87Met	missense_variant	Exon 4 of 6	1	NM_001145784.2	ENSP00000425864.1
BORCS8-MEF2B	ENST00000514819.7	c.-46G>A		5_prime_UTR_variant	Exon 2 of 9	5		ENSP00000454967.3

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000163 AC: 25 AN: 153078 Hom.: 0 AF XY: 0.000209 AC XY: 17 AN XY: 81308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000459

Gnomad SAS exome AF: 0.000527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000679

Gnomad OTH exome AF: 0.000924

GnomAD4 exome AF: 0.000121 AC: 169 AN: 1399102 Hom.: 0 Cov.: 30 AF XY: 0.000161 AC XY: 111 AN XY: 690056

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000199

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.000732

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000259

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000168 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259G>A (p.V87M) alteration is located in exon 4 (coding exon 4) of the BORCS8 gene. This alteration results from a G to A substitution at nucleotide position 259, causing the valine (V) at amino acid position 87 to be replaced by a methionine (M). 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
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.94	P;.;P
Vest4		0.47
MutPred		0.63		Gain of MoRF binding (P = 0.0972);.;Gain of MoRF binding (P = 0.0972);
MVP		0.085
ClinPred		0.076	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs566625799; hg19: chr19-19293449; COSMIC: COSV50765913; COSMIC: COSV50765913;