NM_000152.5:c.858G>A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000152.5(GAA):c.858G>A(p.Thr286Thr) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000133 in 1,349,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000152.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000915 AC: 1AN: 109332Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000209 AC: 3AN: 143204Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 77032
GnomAD4 exome AF: 0.0000137 AC: 17AN: 1239742Hom.: 0 Cov.: 36 AF XY: 0.0000147 AC XY: 9AN XY: 614208
GnomAD4 genome AF: 0.00000914 AC: 1AN: 109426Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 52600
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:2Uncertain:1
This sequence change affects codon 286 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201056962, gnomAD 0.003%). This variant has been observed in individual(s) with late-onset Pompe disease (PMID: 35123877). 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: 572952). 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at