rs778032599
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000152.5(GAA):c.2799+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
GAA
NM_000152.5 splice_donor_region, intron
NM_000152.5 splice_donor_region, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.79
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-80118809-A-G is Pathogenic according to our data. Variant chr17-80118809-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 286228.Status of the report is reviewed_by_expert_panel, 3 stars.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.2799+4A>G | splice_donor_region_variant, intron_variant | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.2799+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249970Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135324
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1460630Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 726590
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:3Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 17, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2022 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Jun 27, 2023 | The NM_000152.5:c.2799+4A>G is located in the donor splice site region of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.62 for donor loss, predicting that the variant disrupts the donor splice site of this intron (PP3). Two individuals with Pompe disease have been reported to have this variant; one has documentation of deficient GAA activity and is on enzyme replacement therapy (PMID: 26873529) (PP4_Moderate), and the second patient has limb girdle muscular dystrophy (PMID: 30564623). Both individuals are compound heterozygous for this variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.1548G>A (p.Trp516Ter) (PMID: 26873529) or c.2501_2502delCA (PMID: 30564623); the phase is unknown in each case (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16172 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Additional variants in this splice region have been identified, including c.2799+2C>T, c.2799+2C>A, and c.2799+5G>A (PMID: 28265479); all currently classified by the ClinGen LD VCEP as variants of uncertain significance. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change falls in intron 19 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs778032599, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of GAA-related conditions (PMID: 26873529, 30564623; Invitae). 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: 286228). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 23, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 19, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at