rs771069887

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000642.3(AGL):โ€‹c.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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.28
Variant links:
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 1-99892561-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
AGLNM_000642.3 linkuse as main transcriptc.3216_3217delGA p.Glu1072fs frameshift_variant 24/34 ENST00000361915.8 NP_000633.2 P35573-1A0A0S2A4E4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGLENST00000361915.8 linkuse as main transcriptc.3216_3217delGA p.Glu1072fs frameshift_variant 24/341 NM_000642.3 ENSP00000355106.3 P35573-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251206
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461374
Hom.:
0
AF XY:
0.00000413
AC XY:
3
AN XY:
726994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152270
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

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 submitterclinical testingBaylor GeneticsJan 22, 2024- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 08, 2022- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This 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 providedclinical testingCounsylJul 11, 2015- -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The 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 submitterclinical testingEurofins Ntd Llc (ga)Sep 28, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 13, 2022Not 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 30, 2016Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771069887; hg19: chr1-100358117; API