rs777393482
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000642.3(AGL):c.1577A>G(p.Asp526Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,980 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
AGL
NM_000642.3 missense
NM_000642.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 8.88
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a active_site (size 0) in uniprot entity GDE_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.989
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.1577A>G | p.Asp526Gly | missense_variant | 12/34 | ENST00000361915.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.1577A>G | p.Asp526Gly | missense_variant | 12/34 | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251222Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135772
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461758Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727176
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease type III Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 526 of the AGL protein (p.Asp526Gly). This variant is present in population databases (rs777393482, gnomAD 0.002%). This missense change has been observed in individual(s) with glycogen storage disease type III (PMID: 27106217). ClinVar contains an entry for this variant (Variation ID: 526603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 06, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
T;T;T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;D;D;D
Vest4
MutPred
Loss of stability (P = 0.0269);Loss of stability (P = 0.0269);Loss of stability (P = 0.0269);Loss of stability (P = 0.0269);.;
MVP
MPC
0.33
ClinPred
D
GERP RS
Varity_R
gMVP
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