Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000642.3(AGL):c.1481G>A(p.Arg494His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,613,946 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R494C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0072 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 84 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.71

Publications

19 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.01898399).

BP6

Variant 1-99877698-G-A is Benign according to our data. Variant chr1-99877698-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00719 (1094/152200) while in subpopulation NFE AF = 0.00907 (617/68004). AF 95% confidence interval is 0.00848. There are 11 homozygotes in GnomAd4. There are 601 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 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.1481G>A	p.Arg494His	missense	Exon 12 of 34	NP_000633.2
AGL	NM_000028.3		c.1481G>A	p.Arg494His	missense	Exon 12 of 34	NP_000019.2
AGL	NM_000643.3		c.1481G>A	p.Arg494His	missense	Exon 12 of 34	NP_000634.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGL	ENST00000361915.8	TSL:1 MANE Select	c.1481G>A	p.Arg494His	missense	Exon 12 of 34	ENSP00000355106.3
AGL	ENST00000294724.8	TSL:1	c.1481G>A	p.Arg494His	missense	Exon 12 of 34	ENSP00000294724.4
AGL	ENST00000370163.7	TSL:1	c.1481G>A	p.Arg494His	missense	Exon 12 of 34	ENSP00000359182.3

Frequencies

GnomAD3 genomes

AF:

0.00720

AC:

1095

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0338

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00907

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00843

AC:

2119

AN:

251244

AF XY:

0.00874

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00735

GnomAD4 exome

AF:

0.00839

AC:

12269

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00839

AC XY:

6103

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33476

American (AMR)

AF:

0.00266

AC:

119

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000985

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0301

AC:

1610

AN:

53418

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00892

AC:

9916

AN:

1111926

Other (OTH)

AF:

0.00667

AC:

403

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

624

1247

1871

2494

3118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.00719

AC:

1094

AN:

152200

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

601

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41522

American (AMR)

AF:

0.00235

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0338

AC:

358

AN:

10588

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00907

AC:

617

AN:

68004

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00761

Hom.:

Bravo

AF:

0.00475

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00837

AC:

ExAC

AF:

0.00888

AC:

1078

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00780

EpiControl

AF:

0.00699

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease type III (5)

not provided (4)

not specified (3)

AGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.0040

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.019

MetaSVM

Pathogenic

0.79

MutationAssessor

Pathogenic

3.5

PhyloP100

7.7

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.80

MVP

0.94

MPC

0.32

ClinPred

0.049

GERP RS

5.1

Varity_R

0.55

gMVP

0.86

Mutation Taster

=99/1

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

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

rs141043166

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over