rs786204481
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000642.3(AGL):c.2309-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,610,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000642.3 splice_acceptor
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 |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.2309-1G>A | splice_acceptor_variant | ENST00000361915.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.2309-1G>A | splice_acceptor_variant | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250122Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135398
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1458242Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 725492
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74250
ClinVar
Submissions by phenotype
Glycogen storage disease type III Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change affects an acceptor splice site in intron 17 of the AGL 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 AGL are known to be pathogenic (PMID: 19299494). This variant is present in population databases (rs786204481, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with glycogen storage disease III (PMID: 20648714, 27460348, 34820282). ClinVar contains an entry for this variant (Variation ID: 188804). 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 | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 10, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 27, 2014 | - - |
Glycogen storage disease IIIa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 13, 2017 | Variant summary: The c.2309-1G>A (aka IVS17-1G>A) in a AGL gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical acceptor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from control dataset of ExAC (~120120 chrs tested), but is present at a low frequency in gnomAD dataset (2/245384 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.00228. The variant has been reported in affected individuals with enzymatically confirmed dx of GSDIII via publications and is cited as Likely Pathogenic by a reputable database/clinical laboratory. Taken together, the variant was classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at