17-80110725-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000152.5(GAA):c.1438-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000152.5 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1438-2A>G | splice_acceptor_variant | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1438-2A>G | splice_acceptor_variant | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461322Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1AN XY: 726988
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 01, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 24158270). ClinVar contains an entry for this variant (Variation ID: 526521). Disruption of this splice site has been observed in individual(s) with late onset glycogen storage disease type II (PMID: 24158270). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 21, 2017 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Mar 30, 2020 | The c.1438-2A>G variant alters the canonical acceptor splice site of intron 9 and has been shown by RT-PCR to causing skipping of exon 10, resulting in an in frame deletion that removes about 4% of the gene product (PMID 24158270). Exon 10 forms part of the GAA catalytic barrel, including two residues, Trp481 and Trp516, which are part of the GAA active site (PMIDs 1856189; 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity, and PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two individuals with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4, and who are compound heterozygotes for this variant and a second pathogenic variant, c.-32-13T>G in one case (PMIDs 24158270), and c.955+1G>A in the other (PMID 29422078), meeting PM3. Other variants altering the same canonical splice site, c.1438-1G>T (PMID 18425781) and c.1438-1G>C (PMIDs 22538254, 24495340), have been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 526521) with one submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at