rs17121403

Positions:

chr1-99870421-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000642.3(AGL):c.686A>G(p.Gln229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,613,906 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 259 hom., cov: 32)

Exomes 𝑓: 0.022 ( 710 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.68

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:

AGL (HGNC:):

AGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018741786).

BP6

Variant 1-99870421-A-G is Benign according to our data. Variant chr1-99870421-A-G is described in ClinVar as [Benign]. Clinvar id is 256749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3 linkuse as main transcript	c.686A>G	p.Gln229Arg	missense_variant	6/34	ENST00000361915.8	NP_000633.2	P35573-1A0A0S2A4E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 linkuse as main transcript	c.686A>G	p.Gln229Arg	missense_variant	6/34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.0426

AC:

6475

AN:

152160

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0953

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0599

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.0333

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00461

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0416

GnomAD3 exomes

AF:

0.0338

AC:

8504

AN:

251232

Hom.:

333

AF XY:

0.0291

AC XY:

3951

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.0945

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.0269

Gnomad SAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.00582

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0222

AC:

32486

AN:

1461628

Hom.:

710

Cov.:

AF XY:

0.0213

AC XY:

15520

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.0968

Gnomad4 AMR exome

AF:

0.0985

Gnomad4 ASJ exome

AF:

0.00781

Gnomad4 EAS exome

AF:

0.0389

Gnomad4 SAS exome

AF:

0.0205

Gnomad4 FIN exome

AF:

0.00646

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0233

GnomAD4 genome

AF:

0.0428

AC:

6513

AN:

152278

Hom.:

259

Cov.:

AF XY:

0.0430

AC XY:

3199

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0959

Gnomad4 AMR

AF:

0.0601

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.0334

Gnomad4 SAS

AF:

0.0190

Gnomad4 FIN

AF:

0.00461

Gnomad4 NFE

AF:

0.0168

Gnomad4 OTH

AF:

0.0412

Alfa

AF:

0.0234

Hom.:

176

Bravo

AF:

0.0511

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.0876

AC:

386

ESP6500EA

AF:

0.0188

AC:

162

ExAC

AF:

0.0326

AC:

3953

Asia WGS

AF:

0.0350

AC:

121

AN:

3476

EpiCase

AF:

0.0168

EpiControl

AF:

0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2015	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

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.029

T;T;T;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.86

D;.;.;.;D

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.71

N;N;N;N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.40

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.86

T;T;T;T;T

Sift4G

Benign

0.53

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.043

MPC

0.043

ClinPred

0.0016

GERP RS

4.2

Varity_R

0.039

gMVP

0.59

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

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