NM_000642.3:c.3199C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000642.3(AGL):c.3199C>T(p.Pro1067Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,612,830 control chromosomes in the GnomAD database, including 16,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1067L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1508 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15018 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.28

Publications

30 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=0.0034675002).

BP6

Variant 1-99892547-C-T is Benign according to our data. Variant chr1-99892547-C-T is described in ClinVar as Benign. ClinVar VariationId is 256734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.3199C>T	p.Pro1067Ser	missense_variant	Exon 24 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.3199C>T	p.Pro1067Ser	missense_variant	Exon 24 of 34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20704

AN:

151914

Hom.:

1507

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.0262

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.148

GnomAD2 exomes

AF:

0.134

AC:

33763

AN:

251154

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.0998

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.167

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.141

AC:

205269

AN:

1460798

Hom.:

15018

Cov.:

AF XY:

0.141

AC XY:

102608

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.119

AC:

3984

AN:

33442

American (AMR)

AF:

0.105

AC:

4681

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

4844

AN:

26104

East Asian (EAS)

AF:

0.0303

AC:

1201

AN:

39614

South Asian (SAS)

AF:

0.144

AC:

12420

AN:

86230

European-Finnish (FIN)

AF:

0.169

AC:

9024

AN:

53402

Middle Eastern (MID)

AF:

0.233

AC:

1341

AN:

5762

European-Non Finnish (NFE)

AF:

0.143

AC:

159327

AN:

1111210

Other (OTH)

AF:

0.140

AC:

8447

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

9117

18234

27351

36468

45585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5702

11404

17106

22808

28510

<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:

0.136

AC:

20697

AN:

152032

Hom.:

1508

Cov.:

AF XY:

0.137

AC XY:

10206

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.120

AC:

4983

AN:

41508

American (AMR)

AF:

0.126

AC:

1930

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

632

AN:

3468

East Asian (EAS)

AF:

0.0263

AC:

136

AN:

5174

South Asian (SAS)

AF:

0.150

AC:

722

AN:

4820

European-Finnish (FIN)

AF:

0.169

AC:

1789

AN:

10566

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.146

AC:

9945

AN:

67920

Other (OTH)

AF:

0.145

AC:

306

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

907

1814

2720

3627

4534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.139

Hom.:

5273

Bravo

AF:

0.129

TwinsUK

AF:

0.137

AC:

508

ALSPAC

AF:

0.142

AC:

548

ESP6500AA

AF:

0.126

AC:

557

ESP6500EA

AF:

0.146

AC:

1257

ExAC

AF:

0.136

AC:

16506

Asia WGS

AF:

0.0940

AC:

327

AN:

3476

EpiCase

AF:

0.157

EpiControl

AF:

0.157

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Benign:4

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.22

T;T;T;T;.

Eigen

Benign

-0.021

Eigen_PC

Benign

0.034

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;.;.;.;D

MetaRNN

Benign

0.0035

T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.6

L;L;L;L;.

PhyloP100

7.3

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.027

D;D;D;D;D

Sift4G

Uncertain

0.048

D;D;D;D;T

Polyphen

0.15

B;B;B;B;B

Vest4

0.42

MPC

0.048

ClinPred

0.078

GERP RS

5.2

Varity_R

0.17

gMVP

0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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