NM_000152.5:c.547-4C>G

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 highest continental population minor allele frequency for c.547-4C>G in gnomAD v2.1.1 is 0.7403 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77927) and European Finnish (0.75914) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92485, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145784/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.66 ( 33579 hom., cov: 32)

Exomes 𝑓: 0.71 ( 372392 hom. )

Consequence

GAA
NM_000152.5 splice_region, intron

Scores

Splicing: ADA: 0.00004151

Clinical Significance

Benign reviewed by expert panel U:1B:15

Conservation

PhyloP100: -0.139

Publications

23 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.547-4C>G		splice_region_variant, intron_variant	Intron 2 of 19	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.547-4C>G		splice_region_variant, intron_variant	Intron 2 of 19	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99789

AN:

151900

Hom.:

33566

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:

0.658

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.667

GnomAD2 exomes

AF:

0.669

AC:

166767

AN:

249394

AF XY:

0.683

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:

0.759

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.712

AC:

1037625

AN:

1457634

Hom.:

372392

Cov.:

AF XY:

0.713

AC XY:

517028

AN XY:

725362

show subpopulations

African (AFR)

AF:

0.539

AC:

18025

AN:

33430

American (AMR)

AF:

0.489

AC:

21878

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

20433

AN:

26122

East Asian (EAS)

AF:

0.560

AC:

22205

AN:

39682

South Asian (SAS)

AF:

0.670

AC:

57728

AN:

86214

European-Finnish (FIN)

AF:

0.763

AC:

39196

AN:

51352

Middle Eastern (MID)

AF:

0.798

AC:

4589

AN:

5750

European-Non Finnish (NFE)

AF:

0.730

AC:

810788

AN:

1110078

Other (OTH)

AF:

0.710

AC:

42783

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

Heterozygous variant carriers

17196

34391

51587

68782

85978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19864

39728

59592

79456

99320

<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:

0.657

AC:

99831

AN:

152018

Hom.:

33579

Cov.:

AF XY:

0.654

AC XY:

48619

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.536

AC:

22194

AN:

41430

American (AMR)

AF:

0.558

AC:

8531

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

2672

AN:

3468

East Asian (EAS)

AF:

0.540

AC:

2792

AN:

5166

South Asian (SAS)

AF:

0.657

AC:

3168

AN:

4824

European-Finnish (FIN)

AF:

0.775

AC:

8196

AN:

10572

Middle Eastern (MID)

AF:

0.847

AC:

249

AN:

294

European-Non Finnish (NFE)

AF:

0.736

AC:

50030

AN:

67958

Other (OTH)

AF:

0.667

AC:

1407

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1718

3436

5154

6872

8590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.707

Hom.:

9153

Bravo

AF:

0.638

Asia WGS

AF:

0.580

AC:

2020

AN:

3478

EpiCase

AF:

0.741

EpiControl

AF:

0.741

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Nov 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The highest continental population minor allele frequency for c.547-4C>G in gnomAD v2.1.1 is 0.7403 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77927) and European Finnish (0.75914) populations. These allele frequencies are higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92485, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -

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. -

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

- -

Sep 04, 2018

Eurofins Ntd Llc (ga)

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

- -

PreventionGenetics, part of Exact Sciences

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

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

- -

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

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: 77.996% 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.6 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.6

(source)

DANN

Benign

0.53

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000042

dbscSNV1_RF

Benign

0.0

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