17-80107862-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.921A>T (p.Ala307=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.23520 (569/24196 alleles, with 666 homozygotes) in the African population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92490; 2 star review status) with eight submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel (Specification Version 2.0): BA1.(Classification approved: August 17, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145795/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.11 ( 1321 hom., cov: 33)

Exomes 𝑓: 0.067 ( 4151 hom. )

Consequence

GAA
NM_000152.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:16

Conservation

PhyloP100: -0.320

Publications

17 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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.921A>T	p.Ala307Ala	synonymous_variant	Exon 5 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.921A>T	p.Ala307Ala	synonymous_variant	Exon 5 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16531

AN:

152078

Hom.:

1320

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0583

Gnomad ASJ

AF:

0.0706

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0740

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0662

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.0720

AC:

17622

AN:

244632

AF XY:

0.0713

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.0727

Gnomad EAS exome

AF:

0.000448

Gnomad FIN exome

AF:

0.0604

Gnomad NFE exome

AF:

0.0652

Gnomad OTH exome

AF:

0.0821

GnomAD4 exome

AF:

0.0670

AC:

97746

AN:

1459232

Hom.:

4151

Cov.:

AF XY:

0.0676

AC XY:

49037

AN XY:

725904

show subpopulations

African (AFR)

AF:

0.238

AC:

7971

AN:

33444

American (AMR)

AF:

0.0516

AC:

2300

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.0713

AC:

1860

AN:

26104

East Asian (EAS)

AF:

0.000328

AC:

AN:

39654

South Asian (SAS)

AF:

0.0865

AC:

7451

AN:

86152

European-Finnish (FIN)

AF:

0.0623

AC:

3246

AN:

52084

Middle Eastern (MID)

AF:

0.130

AC:

701

AN:

5378

European-Non Finnish (NFE)

AF:

0.0627

AC:

69677

AN:

1111610

Other (OTH)

AF:

0.0752

AC:

4527

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5626

11252

16879

22505

28131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2638

5276

7914

10552

13190

<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:

0.109

AC:

16541

AN:

152196

Hom.:

1321

Cov.:

AF XY:

0.107

AC XY:

7988

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.230

AC:

9539

AN:

41510

American (AMR)

AF:

0.0582

AC:

890

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0706

AC:

245

AN:

3470

East Asian (EAS)

AF:

0.000774

AC:

AN:

5170

South Asian (SAS)

AF:

0.0741

AC:

357

AN:

4820

European-Finnish (FIN)

AF:

0.0636

AC:

675

AN:

10616

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0662

AC:

4504

AN:

67990

Other (OTH)

AF:

0.104

AC:

221

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

740

1479

2219

2958

3698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0810

Hom.:

196

Bravo

AF:

0.113

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

EpiCase

AF:

0.0689

EpiControl

AF:

0.0677

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

Jun 04, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Glycogen storage disease, type II

Benign:6

Jun 10, 2021

Genome-Nilou Lab

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

Aug 25, 2021

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000152.5: c.921A>T (p.Ala307=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.23520 (569/24196 alleles, with 666 homozygotes) in the African population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92490; 2 star review status) with eight submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel (Specification Version 2.0): BA1. (Classification approved: August 17, 2021).

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.

Aug 01, 2017

Phosphorus, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Mar 01, 2019

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.7

(source)

DANN

Benign

0.67

PhyloP100

-0.32

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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