rs1278892703
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2_SupportingBP4PM4_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.93_95del variant in GAA is predicted to cause a change in the length of the protein (p.Leu32del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001149 (1/8700 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. PROVEAN and Mutation Taster predict that the variant will have no impact on GAA function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 526535). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, PM4_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 28, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA628018663/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 inframe_deletion
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.93_95del | p.Leu32del | inframe_deletion | 2/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.93_95del | p.Leu32del | inframe_deletion | 2/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 23, 2022 | ClinVar contains an entry for this variant (Variation ID: 526535). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant, c.93_95del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Leu32del), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | May 28, 2023 | The NM_000152.5:c.93_95del variant in GAA is predicted to cause a change in the length of the protein (p.Leu32del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001149 (1/8700 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. PROVEAN and Mutation Taster predict that the variant will have no impact on GAA function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 526535). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, PM4_Supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 28, 2023) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at