chr19-19182640-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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
• 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]

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.17803869).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005919.4. 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
	BORCS8	NM_001145784.2	MANE Select	c.259G>A	p.Val87Met	missense	Exon 4 of 6	NP_001139256.1	Q96FH0-1
	BORCS8-MEF2B	NM_005919.4		c.-173G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_005910.1
	BORCS8	NM_001145783.2		c.259G>A	p.Val87Met	missense	Exon 4 of 4	NP_001139255.1	Q96FH0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BORCS8-MEF2B	ENST00000514819.7	TSL:5	c.-46G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000454967.3	H3BNR1
	BORCS8	ENST00000462790.8	TSL:1 MANE Select	c.259G>A	p.Val87Met	missense	Exon 4 of 6	ENSP00000425864.1	Q96FH0-1
	BORCS8	ENST00000477565.3	TSL:1	c.259G>A	p.Val87Met	missense	Exon 4 of 4	ENSP00000424833.1	Q96FH0-2

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

GnomAD2 exomes AF: 0.000163 AC: 25 AN: 153078 AF XY: 0.000209

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 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

African (AFR) AF: 0.0000633 AC: 2 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25180

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35726

South Asian (SAS) AF: 0.000732 AC: 58 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49044

Middle Eastern (MID) AF: 0.00316 AC: 18 AN: 5696

European-Non Finnish (NFE) AF: 0.0000621 AC: 67 AN: 1078930

Other (OTH) AF: 0.000259 AC: 15 AN: 57996

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

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68004

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.025	D
Polyphen		0.94	P
Vest4		0.47
MutPred		0.63		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
Mutation Taster		=84/16	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: rs566625799; hg19: chr19-19293449; COSMIC: COSV50765913; COSMIC: COSV50765913;