chr7-93994385-C-G

Position:

• chr7-93994385-C-G

Variant summary

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

The NM_005868.6(BET1):​c.202G>C​(p.Asp68His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BET1 NM_005868.6 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.44

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

LOC107986820 (HGNC:):

ACMG classification

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	c.202G>C	p.Asp68His	missense_variant, splice_region_variant	4/4	ENST00000222547.8	NP_005859.1
LOC107986820	XR_001745270.3	n.4248+2219C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BET1	ENST00000222547.8	c.202G>C	p.Asp68His	missense_variant, splice_region_variant	4/4	1	NM_005868.6	ENSP00000222547	P1
BET1-AS1	ENST00000426634.1	n.481+2219C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

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.Asp68His variant in BET1 was identified by our study in trans with a VUS frameshift variant in one individual with progressive muscular weakness and seizures. This variant was absent from large population studies. Transcriptome analysis revealed that this variant was present in the WES & WGS data but not detectable in the patient's muscle RNA sequencing, indicating that there may be allele specific expression of this variant. This variant is located in the first base of the exon 4 (out of 4 exons), which is part of the 3'/5' splice region. While this variant is located in the last exon of the gene, exon 4 encompasses >40% of the coding region of BET1. Additional analysis of the RNA data from this patient also suggested allele imbalance. Instead of matching the expected 50/50 ratio, the allele balance for the compound heterozygous frameshift variant was skewed towards the frameshift by approximately 65%. This suggests that the missense variant may interfere with normal splicing. However, this information is not predictive enough to determine pathogenicity. 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
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.31	B;.
Vest4		0.45
MutPred		0.70		Loss of disorder (P = 0.1166);Loss of disorder (P = 0.1166);
MVP		0.63
MPC		0.55
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.67
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.42		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1562806584; hg19: chr7-93623697;