GeneBe

rs576969969

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000642.3(AGL):ā€‹c.1933A>Gā€‹(p.Thr645Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000508 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000053 ( 0 hom., cov: 33)
Exomes š‘“: 0.000051 ( 0 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.55
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06758392).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGLNM_000642.3 linkc.1933A>G p.Thr645Ala missense_variant Exon 15 of 34 ENST00000361915.8 NP_000633.2 P35573-1A0A0S2A4E4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGLENST00000361915.8 linkc.1933A>G p.Thr645Ala missense_variant Exon 15 of 34 1 NM_000642.3 ENSP00000355106.3 P35573-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000995
AC:
25
AN:
251170
Hom.:
0
AF XY:
0.0000884
AC XY:
12
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000793
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000506
AC:
74
AN:
1461664
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.000153
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glycogen storage disease type III Uncertain:4Benign:1
Jul 27, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 20, 2024
3billion
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Nov 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 645 of the AGL protein (p.Thr645Ala). This variant is present in population databases (rs576969969, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with AGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 526566). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AGL protein function. 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. -

Jan 24, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 15, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
13
DANN
Benign
0.14
DEOGEN2
Benign
0.085
T;T;T;T;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.80
T;.;.;.;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.068
T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-2.7
N;N;N;N;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
3.1
N;N;N;N;N
REVEL
Benign
0.22
Sift
Benign
1.0
T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0
B;B;B;B;B
Vest4
0.41
MutPred
0.60
Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);.;
MVP
0.72
MPC
0.041
ClinPred
0.046
T
GERP RS
4.8
Varity_R
0.050
gMVP
0.42

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: rs576969969; hg19: chr1-100346665; API