rs2230307

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_000642.3(AGL):c.3343G>A(p.Gly1115Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0576 in 1,613,468 control chromosomes in the GnomAD database, including 3,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1115G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.056 ( 344 hom., cov: 32)

Exomes 𝑓: 0.058 ( 3413 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.58

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP6

Variant 1-99896369-G-A is Benign according to our data. Variant chr1-99896369-G-A is described in ClinVar as [Benign]. Clinvar id is 256738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99896369-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.3343G>A	p.Gly1115Arg	missense_variant	Exon 25 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.3343G>A	p.Gly1115Arg	missense_variant	Exon 25 of 34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.0562

AC:

8550

AN:

152086

Hom.:

342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.0496

Gnomad FIN

AF:

0.0728

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0508

Gnomad OTH

AF:

0.0612

GnomAD3 exomes

AF:

0.0735

AC:

18478

AN:

251422

Hom.:

1141

AF XY:

0.0672

AC XY:

9127

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0283

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.158

Gnomad SAS exome

AF:

0.0480

Gnomad FIN exome

AF:

0.0699

Gnomad NFE exome

AF:

0.0489

Gnomad OTH exome

AF:

0.0572

GnomAD4 exome

AF:

0.0577

AC:

84341

AN:

1461264

Hom.:

3413

Cov.:

AF XY:

0.0566

AC XY:

41177

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0278

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.185

Gnomad4 SAS exome

AF:

0.0479

Gnomad4 FIN exome

AF:

0.0700

Gnomad4 NFE exome

AF:

0.0510

Gnomad4 OTH exome

AF:

0.0559

GnomAD4 genome

AF:

0.0562

AC:

8556

AN:

152204

Hom.:

344

Cov.:

AF XY:

0.0586

AC XY:

4361

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0287

Gnomad4 AMR

AF:

0.121

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.162

Gnomad4 SAS

AF:

0.0492

Gnomad4 FIN

AF:

0.0728

Gnomad4 NFE

AF:

0.0508

Gnomad4 OTH

AF:

0.0597

Alfa

AF:

0.0507

Hom.:

449

Bravo

AF:

0.0599

TwinsUK

AF:

0.0564

AC:

209

ALSPAC

AF:

0.0446

AC:

172

ESP6500AA

AF:

0.0261

AC:

115

ESP6500EA

AF:

0.0498

AC:

428

ExAC

AF:

0.0688

AC:

8357

Asia WGS

AF:

0.111

AC:

384

AN:

3478

EpiCase

AF:

0.0436

EpiControl

AF:

0.0412

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

Jan 13, 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

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

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

- -

Jan 29, 2016

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

Oct 26, 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;T;T;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;.;.;D

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.1

M;M;M;M;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.4

D;D;D;D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.040

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.45

MutPred

0.59

Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);.;

MPC

0.31

ClinPred

0.057

GERP RS

5.9

Varity_R

0.83

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.36

Position offset: 19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over