rs147165298

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000642.3(AGL):c.3203A>G(p.Tyr1068Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,624 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y1068Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.57

Publications

2 publications found

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]

AGL Gene-Disease associations (from GenCC):

glycogen storage disease III
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

AGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0116404).

BP6

Variant 1-99892551-A-G is Benign according to our data. Variant chr1-99892551-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (266/152256) while in subpopulation AFR AF = 0.00599 (249/41560). AF 95% confidence interval is 0.00538. There are 3 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.3203A>G	p.Tyr1068Cys	missense_variant	Exon 24 of 34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 link	c.3203A>G	p.Tyr1068Cys	missense_variant	Exon 24 of 34	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.00239

GnomAD2 exomes

AF:

0.000462

AC:

116

AN:

251198

AF XY:

0.000405

show subpopulations

Gnomad AFR exome

AF:

0.00585

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000164

AC:

240

AN:

1461368

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00547

AC:

183

AN:

33454

American (AMR)

AF:

0.000425

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.000177

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111712

Other (OTH)

AF:

0.000364

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00175

AC:

266

AN:

152256

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00599

AC:

249

AN:

41560

American (AMR)

AF:

0.000720

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67986

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000692

Hom.:

Bravo

AF:

0.00182

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000684

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGL: BP4, BS2 -

Mar 02, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease type III

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AGL-related disorder

Benign:1

Aug 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.13

T;T;T;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.81

T;.;.;.;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

M;M;M;M;.

PhyloP100

2.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.37

N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.18

T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.27

MVP

0.77

MPC

0.048

ClinPred

0.011

GERP RS

2.8

Varity_R

0.046

gMVP

0.74

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over