rs886043399
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000152.5(GAA):c.1754+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,902 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_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1754+1G>A | splice_donor_variant | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1754+1G>A | splice_donor_variant | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460692Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726762
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change affects a donor splice site in intron 12 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 19775921). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 286458). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 11, 2020 | Variant summary: GAA c.1754+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251118 control chromosomes. c.1754+1G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), and in at least one case the patient was reported as being cross reactive immunological material (CRIM)-negative (Bali_2012, Kishnani_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the variant being a null allele (PVS1), absent in the gnomad database (PM2), and present in a patient in trans with a pathogenic variant (PM3), this variant has been classified pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Feb 05, 2020 | The c.1754+1G>A variant alters the canonical donor splice site of intron 12 and is predicted to cause skipping of exon 12, which would result in a frameshift, creation of a premature stop codon, and nonsense-mediated decay. This is supported by the finding of no cross reactive immunological material in fibroblasts from a patient with this variant (PMID: 22252923). Therefore PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in a patient with infantile onset Pompe disease in trans with a frameshift variant, c.722_723delTT (PMID 19775921), meeting PM3. There is a ClinVar entry for this variant (Variant ID: 286458; one star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 12, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Oct 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at