rs773095419
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000642.3(AGL):c.2728C>T(p.Arg910Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
AGL
NM_000642.3 stop_gained
NM_000642.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.45
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
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-99888024-C-T is Pathogenic according to our data. Variant chr1-99888024-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 555290.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.2728C>T | p.Arg910Ter | stop_gained | 21/34 | ENST00000361915.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.2728C>T | p.Arg910Ter | stop_gained | 21/34 | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251144Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135726
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461154Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726874
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
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 | Dec 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Human Genetics | Jun 26, 2020 | disease causing - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change creates a premature translational stop signal (p.Arg910*) 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 (rs773095419, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 16705713). ClinVar contains an entry for this variant (Variation ID: 555290). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at