1-99884201-A-G
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000642.3(AGL):āc.2390A>Gā(p.Asn797Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,613,298 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0020 ( 3 hom., cov: 32)
Exomes š: 0.0029 ( 14 hom. )
Consequence
AGL
NM_000642.3 missense
NM_000642.3 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 8.63
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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.020510167).
BP6
Variant 1-99884201-A-G is Benign according to our data. Variant chr1-99884201-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456470.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=3, not_provided=2}. Variant chr1-99884201-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00205 (312/152328) while in subpopulation NFE AF= 0.00284 (193/67994). AF 95% confidence interval is 0.00251. There are 3 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.2390A>G | p.Asn797Ser | missense_variant | 18/34 | ENST00000361915.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.2390A>G | p.Asn797Ser | missense_variant | 18/34 | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00205 AC: 312AN: 152210Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00176 AC: 441AN: 250870Hom.: 1 AF XY: 0.00186 AC XY: 252AN XY: 135600
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GnomAD4 exome AF: 0.00291 AC: 4254AN: 1460970Hom.: 14 Cov.: 31 AF XY: 0.00282 AC XY: 2050AN XY: 726850
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GnomAD4 genome AF: 0.00205 AC: 312AN: 152328Hom.: 3 Cov.: 32 AF XY: 0.00177 AC XY: 132AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:3Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glycogen storage disease type III Uncertain:5Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 11-03-2017 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 31, 2019 | - - |
not provided Uncertain:3Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 28, 2023 | The AGL c.2390A>G; p.Asn797Ser variant (rs149210307), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 456470). This variant is found in the general population with an overall allele frequency of 0.2% (477/282272 alleles, including one homozygote) in the Genome Aggregation Database. The asparagine at codon 797 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.195). Based on available information, the clinical significance of this variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 04, 2021 | This variant is associated with the following publications: (PMID: 25741868, 28492532) - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely benign and reported on 11-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
AGL-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;.;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Benign
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
P;P;P;P;P
Vest4
MVP
MPC
0.13
ClinPred
T
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