Genetic Variant AGL:p.Arg961Arg (chr1-99891290-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000642.3(AGL):c.2883A>G(p.Arg961Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,613,730 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

AGL
NM_000642.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.89

Publications

0 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 1-99891290-A-G is Benign according to our data. Variant chr1-99891290-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.89 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00349 (531/152200) while in subpopulation AFR AF = 0.0123 (510/41546). AF 95% confidence interval is 0.0114. There are 4 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGL	NM_000642.3	MANE Select	c.2883A>G	p.Arg961Arg	synonymous	Exon 22 of 34	NP_000633.2
AGL	NM_000028.3		c.2883A>G	p.Arg961Arg	synonymous	Exon 22 of 34	NP_000019.2
AGL	NM_000643.3		c.2883A>G	p.Arg961Arg	synonymous	Exon 22 of 34	NP_000634.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGL	ENST00000361915.8	TSL:1 MANE Select	c.2883A>G	p.Arg961Arg	synonymous	Exon 22 of 34	ENSP00000355106.3
AGL	ENST00000294724.8	TSL:1	c.2883A>G	p.Arg961Arg	synonymous	Exon 22 of 34	ENSP00000294724.4
AGL	ENST00000370163.7	TSL:1	c.2883A>G	p.Arg961Arg	synonymous	Exon 22 of 34	ENSP00000359182.3

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

527

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.0000294

Gnomad OTH

AF:

0.00432

GnomAD2 exomes

AF:

0.000943

AC:

237

AN:

251206

AF XY:

0.000641

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000400

AC:

584

AN:

1461530

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

255

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.0126

AC:

421

AN:

33466

American (AMR)

AF:

0.000582

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111776

Other (OTH)

AF:

0.00106

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00349

AC:

531

AN:

152200

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0123

AC:

510

AN:

41546

American (AMR)

AF:

0.000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67966

Other (OTH)

AF:

0.00427

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

122

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:

0.00148

Hom.:

Bravo

AF:

0.00402

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 04, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

Apr 26, 2016

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Glycogen storage disease type III

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

1.9

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over