1-99916498-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_000642.3(AGL):c.4347+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,242 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_000642.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.4347+1G>A | splice_donor_variant | ENST00000361915.8 | |||
LOC124904230 | XR_007066249.1 | n.1146-3281C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.4347+1G>A | splice_donor_variant | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457242Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725146
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease type III Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 12, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2023 | Disruption of this splice site has been observed in individual(s) with glycogen storage disease (PMID: 26984562; Invitae). ClinVar contains an entry for this variant (Variation ID: 456505). Studies have shown that disruption of this splice site results in skipping of exon 33 and introduces a new termination codon (PMID: 26984562). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 32 of the AGL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at