rs137852894
Positions:
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.Trp548Ter) 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GBE1
NM_000158.4 stop_gained
NM_000158.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.50
Genes affected
GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-81537071-C-T is Pathogenic according to our data. Variant chr3-81537071-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2793.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBE1 | NM_000158.4 | c.1643G>A | p.Trp548Ter | stop_gained | 13/16 | ENST00000429644.7 | |
GBE1 | XR_007095662.1 | n.1771G>A | non_coding_transcript_exon_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBE1 | ENST00000429644.7 | c.1643G>A | p.Trp548Ter | stop_gained | 13/16 | 1 | NM_000158.4 | P1 | |
GBE1 | ENST00000489715.1 | c.1520G>A | p.Trp507Ter | stop_gained | 13/16 | 2 | |||
GBE1 | ENST00000484687.1 | n.44G>A | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000106 AC: 2AN: 188268Hom.: 0 AF XY: 0.0000193 AC XY: 2AN XY: 103568
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GnomAD4 exome AF: 0.00000144 AC: 2AN: 1393100Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1AN XY: 689962
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glycogen storage disease, type IV Pathogenic:2
Pathogenic, no assertion criteria provided | curation | GeneReviews | Apr 02, 2009 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 27, 2022 | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 21, 2007 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at