rs771069887
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000642.3(AGL):โc.3216_3217delGAโ(p.Glu1072fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (โ โ ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: ๐ 0.000033 ( 0 hom., cov: 33)
Exomes ๐: 0.0000055 ( 0 hom. )
Consequence
AGL
NM_000642.3 frameshift
NM_000642.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.28
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]
Genome browser will be placed here
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
Very rare variant in population databases, with high coverage;
PP5
Variant 1-99892561-TGA-T is Pathogenic according to our data. Variant chr1-99892561-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 432008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.3216_3217delGA | p.Glu1072fs | frameshift_variant | 24/34 | ENST00000361915.8 | NP_000633.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.3216_3217delGA | p.Glu1072fs | frameshift_variant | 24/34 | 1 | NM_000642.3 | ENSP00000355106.3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152152Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
5
AN:
152152
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251206Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135782
GnomAD3 exomes
AF:
AC:
3
AN:
251206
Hom.:
AF XY:
AC XY:
1
AN XY:
135782
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461374Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726994
GnomAD4 exome
AF:
AC:
8
AN:
1461374
Hom.:
AF XY:
AC XY:
3
AN XY:
726994
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152270Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74456
GnomAD4 genome
AF:
AC:
5
AN:
152270
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74456
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease type III Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Glu1072Aspfs*36) 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). This variant is present in population databases (rs771069887, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with glycogen storage disease type III (PMID: 20648714, 22035446, 28888851). ClinVar contains an entry for this variant (Variation ID: 432008). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 11, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.3216_3217del;p.(Glu1072Aspfs*36) is a null frameshift variant (NMD) in the AGL gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 432008; PMID: 20648714; 22035446; 28888851) - PS4. The variant is present at low allele frequencies population databases (rs771069887โ gnomAD 0.003286%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Glu1072Aspfs*36) was detected in trans with a pathogenic variant (PMID: 28888851) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27460348, 19754354, 20648714, 26885414, 23649758, 29809327, 22035446, 23507172, 25602008, 28888851, 31589614) - |
Glycogen storage disease IIIa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 30, 2016 | Variant summary: The AGL c.3216_3217delGA (p.Glu1072Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent AGL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/121086 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822). The variant was reported in numerous affected individuals and was shown to result in no AGL activity in peripheral leukocytes. Taken together, this variant is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at