rs1042393

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000152.5(GAA):c.596A>G(p.His199Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,610,784 control chromosomes in the GnomAD database, including 405,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. H199C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.66 ( 33560 hom., cov: 32)

Exomes 𝑓: 0.71 ( 371799 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:15

Conservation

PhyloP100: -0.0300

Publications

68 publications found

Variant links:

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

glycogen storage disease II
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
glycogen storage disease due to acid maltase deficiency, infantile onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
glycogen storage disease due to acid maltase deficiency, late-onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.

BP4

Computational evidence support a benign effect (MetaRNN=8.970628E-7).

BP6

Variant 17-80105798-A-G is Benign according to our data. Variant chr17-80105798-A-G is described in ClinVar as Benign. ClinVar VariationId is 92486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.596A>G	p.His199Arg	missense_variant	Exon 3 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.596A>G	p.His199Arg	missense_variant	Exon 3 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99760

AN:

151922

Hom.:

33547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.536

Gnomad AMI

AF:

0.649

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.770

Gnomad EAS

AF:

0.540

Gnomad SAS

AF:

0.648

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.669

GnomAD2 exomes

AF:

0.667

AC:

166175

AN:

248970

AF XY:

0.682

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.475

Gnomad ASJ exome

AF:

0.780

Gnomad EAS exome

AF:

0.529

Gnomad FIN exome

AF:

0.758

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.711

AC:

1037403

AN:

1458744

Hom.:

371799

Cov.:

AF XY:

0.712

AC XY:

516674

AN XY:

725778

show subpopulations

African (AFR)

AF:

0.539

AC:

18045

AN:

33470

American (AMR)

AF:

0.489

AC:

21882

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

20443

AN:

26136

East Asian (EAS)

AF:

0.559

AC:

22201

AN:

39690

South Asian (SAS)

AF:

0.662

AC:

57071

AN:

86248

European-Finnish (FIN)

AF:

0.763

AC:

38833

AN:

50862

Middle Eastern (MID)

AF:

0.797

AC:

4588

AN:

5756

European-Non Finnish (NFE)

AF:

0.730

AC:

811548

AN:

1111514

Other (OTH)

AF:

0.709

AC:

42792

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

17725

35450

53174

70899

88624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19904

39808

59712

79616

99520

<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:

0.656

AC:

99802

AN:

152040

Hom.:

33560

Cov.:

AF XY:

0.654

AC XY:

48586

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.536

AC:

22214

AN:

41450

American (AMR)

AF:

0.558

AC:

8525

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

2670

AN:

3468

East Asian (EAS)

AF:

0.540

AC:

2790

AN:

5162

South Asian (SAS)

AF:

0.647

AC:

3120

AN:

4822

European-Finnish (FIN)

AF:

0.775

AC:

8201

AN:

10582

Middle Eastern (MID)

AF:

0.847

AC:

249

AN:

294

European-Non Finnish (NFE)

AF:

0.736

AC:

50030

AN:

67964

Other (OTH)

AF:

0.669

AC:

1411

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1731

3463

5194

6926

8657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.702

Hom.:

70119

Bravo

AF:

0.638

TwinsUK

AF:

0.722

AC:

2678

ALSPAC

AF:

0.724

AC:

2791

ESP6500AA

AF:

0.544

AC:

2398

ESP6500EA

AF:

0.738

AC:

6349

ExAC

AF:

0.674

AC:

81812

Asia WGS

AF:

0.577

AC:

2009

AN:

3478

EpiCase

AF:

0.741

EpiControl

AF:

0.742

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

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. -

Aug 01, 2017

Phosphorus, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.976% in gnomAD_ExomesFounderPop) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.8 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

Oct 19, 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

- -

Cardiovascular phenotype

Benign:1

Dec 11, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.17

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.16

T;.;T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.021

T;T;.;T

MetaRNN

Benign

9.0e-7

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-3.4

.;.;N;N

PhyloP100

-0.030

PrimateAI

Benign

0.28

PROVEAN

Benign

1.7

.;.;N;N

REVEL

Benign

0.18

Sift

Benign

0.70

.;.;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;.;B;B

Vest4

0.015

MPC

0.13

ClinPred

0.012

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

gMVP

0.37

Mutation Taster

=100/0

polymorphism (auto)

(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

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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