rs387906245
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000642.3(AGL):c.4456del(p.Ser1486ProfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1485L) has been classified as Likely benign.
Frequency
Consequence
NM_000642.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.4456del | p.Ser1486ProfsTer18 | frameshift_variant | 33/34 | ENST00000361915.8 | |
LOC124904230 | XR_007066249.1 | n.1146-3487del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.4456del | p.Ser1486ProfsTer18 | frameshift_variant | 33/34 | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250878Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135600
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461100Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726868
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease type III Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 20, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 20, 2019 | NM_000642.2(AGL):c.4456delT(S1486Pfs*18) is classified as pathogenic in the context of glycogen storage disease type III. Sources cited for classification include the following: PMID 9412782 and 25602008. Classification of NM_000642.2(AGL):c.4456delT(S1486Pfs*18) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | This sequence change creates a premature translational stop signal (p.Ser1486Profs*18) in the AGL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the AGL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with glycogen storage disease III (PMID: 9412782, 25388549, 25602008, 27065010, 27460348). This variant is also known as c.4455delT. ClinVar contains an entry for this variant (Variation ID: 1098). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | Founder variant in North African Jewish persons and those of Inuit descent - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 9412782 / 3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25388549 , 9412782 / 3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001098 / PMID: 9412782). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2020 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 47 amino acids are lost and replaced with 17 incorrect amino acids (Stenson et al., 2014);; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31661040, 28888851, 25388549, 25602008, 27460348, 9412782) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2014 | - - |
Glycogen storage disease IIIa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1997 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at