chr3-81537071-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000158.4(GBE1):c.1643G>A(p.Trp548*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,393,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000158.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GBE1 | ENST00000429644.7 | c.1643G>A | p.Trp548* | stop_gained | Exon 13 of 16 | 1 | NM_000158.4 | ENSP00000410833.2 | ||
GBE1 | ENST00000489715.1 | c.1520G>A | p.Trp507* | stop_gained | Exon 13 of 16 | 2 | ENSP00000419638.1 | |||
GBE1 | ENST00000484687.1 | n.44G>A | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000106 AC: 2AN: 188268Hom.: 0 AF XY: 0.0000193 AC XY: 2AN XY: 103568
GnomAD4 exome AF: 0.00000144 AC: 2AN: 1393100Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1AN XY: 689962
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease, type IV Pathogenic:2
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The p.Trp548Ter variant in GBE1 has been reported in 1 individual, in the homozygous state, with glycogen storage disease type IV (GSD IV) (PMID: 1766224) and has been identified in 0.009% (1/11570) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852894). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 2793) and has been interpreted as pathogenic by OMIM and GeneReviews. In vitro functional studies provide some evidence that the p.Trp548Ter variant may impact protein function (PMID: 1766224). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 548, which is predicted to lead to a truncated or absent protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GSD IV. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GSD IV. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting, PS3_moderate, PM3_supporting (Richards 2015). -
Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at