1-99874696-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000642.3(AGL):c.968G>A(p.Arg323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,590,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R323R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 1.03

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004442841).

BP6

Variant 1-99874696-G-A is Benign according to our data. Variant chr1-99874696-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456516.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00118 (175/148334) while in subpopulation AFR AF = 0.00377 (156/41346). AF 95% confidence interval is 0.00329. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.968G>A	p.Arg323Gln	missense_variant	Exon 8 of 34	ENST00000361915.8	NP_000633.2	P35573-1A0A0S2A4E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 link	c.968G>A	p.Arg323Gln	missense_variant	Exon 8 of 34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

174

AN:

148212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00376

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000102

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000152

Gnomad OTH

AF:

0.000498

GnomAD2 exomes

AF:

0.000356

AC:

AN:

250098

AF XY:

0.000296

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000214

AC:

308

AN:

1441942

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

154

AN XY:

717424

show subpopulations

African (AFR)

AF:

0.00363

AC:

121

AN:

33310

American (AMR)

AF:

0.000135

AC:

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24836

East Asian (EAS)

AF:

0.000202

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85840

European-Finnish (FIN)

AF:

0.000234

AC:

AN:

51344

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.000128

AC:

140

AN:

1097768

Other (OTH)

AF:

0.000303

AC:

AN:

59316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00118

AC:

175

AN:

148334

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

72464

show subpopulations

African (AFR)

AF:

0.00377

AC:

156

AN:

41346

American (AMR)

AF:

0.000471

AC:

AN:

14870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3162

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

9832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.000152

AC:

AN:

65976

Other (OTH)

AF:

0.000493

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000468

Hom.:

Bravo

AF:

0.00115

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000453

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000219

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Uncertain:2Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Oct 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The AGL c.968G>A; p.Arg323Gln variant (rs139399527), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 456516). This variant is found in the African/African-American population with an allele frequency of 0.39% (98/24,906 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.052). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGL: BP4 -

Jul 29, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AGL-related disorder

Benign:1

May 05, 2022

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

0.071

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.024

T;T;T;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.015

LIST_S2

Uncertain

0.87

D;.;.;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.0044

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N;N;N;.

PhyloP100

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

0.71

N;N;N;N;N

REVEL

Benign

0.052

Sift

Benign

0.66

T;T;T;T;T

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.17

MVP

0.64

MPC

0.045

ClinPred

0.0036

GERP RS

0.72

Varity_R

0.023

gMVP

0.23

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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