rs1057516741
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000642.3(AGL):βc.1169_1172delβ(p.Asn390IlefsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
AGL
NM_000642.3 frameshift
NM_000642.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.15
Genes affected
AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-99875237-TTAAC-T is Pathogenic according to our data. Variant chr1-99875237-TTAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.1169_1172del | p.Asn390IlefsTer26 | frameshift_variant | 9/34 | ENST00000361915.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.1169_1172del | p.Asn390IlefsTer26 | frameshift_variant | 9/34 | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461682Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727170
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74382
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease type III Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 370750). This variant is also known as c.1117_1120del. This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 11757581). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn390Ilefs*26) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at