chr17-80104538-GCTTTCTT-TCCCTGCTGAGCCTCCTACAGGCCTCCCGC
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_000152.5(GAA):c.-32-17_-32-10delinsTCCCTGCTGAGCCTCCTACAGGCCTCCCGC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
GAA
NM_000152.5 splice_polypyrimidine_tract, intron
NM_000152.5 splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.07
Genes affected
GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-80104538-GCTTTCTT-TCCCTGCTGAGCCTCCTACAGGCCTCCCGC is Pathogenic according to our data. Variant chr17-80104538-GCTTTCTT-TCCCTGCTGAGCCTCCTACAGGCCTCCCGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1980660.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.-32-17_-32-10delinsTCCCTGCTGAGCCTCCTACAGGCCTCCCGC | splice_polypyrimidine_tract_variant, intron_variant | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.-32-17_-32-10delinsTCCCTGCTGAGCCTCCTACAGGCCTCCCGC | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.-32-13T nucleotide in the GAA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2510307, 7881425, 21439876, 22613277, 24245577, 24590251, 26231297). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Pompe disease (PMID: 25037089). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.