Variant 7-93999179-AG-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005868.6(BET1):c.134delC(p.Ala45fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,611,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

BET1
NM_005868.6 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.72

Variant links:

Genes affected

BET1 (HGNC:14562): (Bet1 golgi vesicular membrane trafficking protein) This gene encodes a golgi-associated membrane protein that participates in vesicular transport from the endoplasmic reticulum (ER) to the Golgi complex. The encoded protein functions as a soluble N-ethylaleimide-sensitive factor attachment protein receptor and may be involved in the docking of ER-derived vesicles with the cis-Golgi membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

BET1 links:

BET1-AS1 (HGNC:40690): (BET1 antisense RNA 1)

BET1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BET1	NM_005868.6 link	c.134delC	p.Ala45fs	frameshift_variant	2/4	ENST00000222547.8	NP_005859.1	O15155-1Q53XK0
BET1	NM_001317739.2 link	c.134delC	p.Ala45fs	frameshift_variant	2/5		NP_001304668.1	O15155-2
BET1	NR_133908.2 link	n.273delC		non_coding_transcript_exon_variant	2/7
BET1	NR_133909.2 link	n.273delC		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BET1	ENST00000222547.8 link	c.134delC	p.Ala45fs	frameshift_variant	2/4	1	NM_005868.6	ENSP00000222547.3		O15155-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250582

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000241

AC:

352

AN:

1458962

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

168

AN XY:

725786

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000105

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Muscular dystrophy, congenital, with rapid progression

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 06, 2024

- -

Seizure;C0240421:Progressive muscle weakness

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Feb 25, 2019

The heterozygous p.Ala45ValfsTer2 variant in BET1 was identified by our study in trans with a VUS missense variant in one individual with progressive muscular weakness and seizures. This variant has been identified in 0.018% (24/128800) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs541754296). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 45 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While this alteration is then predicted to lead to a truncated or absent protein, this variant was detectable in the muscle RNA. However, western blot analysis showed reduced to absent BET1 in patient fibroblasts compared to controls. Of note, loss of function of the BET1 gene in autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over