NM_000152.5:c.858+7_858+8insAGCGGGC

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.858+7_858+8insAGCGGGC in gnomAD v.2.1.1 is 0.7353 in the European non-Finnish population. This allele frequency is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.7783) and European Finnish (0.7613) populations. There is a ClinVar entry for this variant (Variation ID: 92489, 2 star review status), with 10 submitters all 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/CA145794/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.65 ( 33224 hom., cov: 0)

Exomes 𝑓: 0.71 ( 370960 hom. )

Consequence

GAA
NM_000152.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: 0.160

Publications

6 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.858+7_858+8insAGCGGGC		splice_region_variant, intron_variant	Intron 4 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.858+5_858+6insGCAGCGG		splice_region_variant, intron_variant	Intron 4 of 19	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.654

AC:

99093

AN:

151582

Hom.:

33211

Cov.:

show subpopulations

Gnomad AFR

AF:

0.529

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.556

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.537

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.836

Gnomad NFE

AF:

0.735

Gnomad OTH

AF:

0.665

GnomAD2 exomes

AF:

0.665

AC:

161447

AN:

242952

AF XY:

0.679

show subpopulations

Gnomad AFR exome

AF:

0.526

Gnomad AMR exome

AF:

0.470

Gnomad ASJ exome

AF:

0.779

Gnomad EAS exome

AF:

0.524

Gnomad FIN exome

AF:

0.762

Gnomad NFE exome

AF:

0.736

Gnomad OTH exome

AF:

0.719

GnomAD4 exome

AF:

0.710

AC:

1036220

AN:

1459002

Hom.:

370960

Cov.:

AF XY:

0.711

AC XY:

516049

AN XY:

725774

show subpopulations

African (AFR)

AF:

0.531

AC:

17770

AN:

33446

American (AMR)

AF:

0.486

AC:

21709

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

20376

AN:

26064

East Asian (EAS)

AF:

0.558

AC:

22131

AN:

39656

South Asian (SAS)

AF:

0.664

AC:

57193

AN:

86168

European-Finnish (FIN)

AF:

0.765

AC:

39858

AN:

52122

Middle Eastern (MID)

AF:

0.795

AC:

4577

AN:

5760

European-Non Finnish (NFE)

AF:

0.729

AC:

809947

AN:

1110886

Other (OTH)

AF:

0.708

AC:

42659

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

19759

39518

59277

79036

98795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19896

39792

59688

79584

99480

<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:

0.654

AC:

99137

AN:

151700

Hom.:

33224

Cov.:

AF XY:

0.651

AC XY:

48279

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.529

AC:

21914

AN:

41406

American (AMR)

AF:

0.555

AC:

8462

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2660

AN:

3458

East Asian (EAS)

AF:

0.537

AC:

2757

AN:

5132

South Asian (SAS)

AF:

0.651

AC:

3127

AN:

4806

European-Finnish (FIN)

AF:

0.775

AC:

8202

AN:

10582

Middle Eastern (MID)

AF:

0.844

AC:

238

AN:

282

European-Non Finnish (NFE)

AF:

0.735

AC:

49797

AN:

67774

Other (OTH)

AF:

0.665

AC:

1398

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1741

3481

5222

6962

8703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

796

1592

2388

3184

3980

<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:

0.672

Hom.:

3729

EpiCase

AF:

0.741

EpiControl

AF:

0.735

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 19, 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.858+7_858+8insAGCGGGC in gnomAD v.2.1.1 is 0.7353 in the European non-Finnish population. This allele frequency is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.7783) and European Finnish (0.7613) populations. There is a ClinVar entry for this variant (Variation ID: 92489, 2 star review status), with 10 submitters all 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. -

Sep 16, 2020

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2017

Phosphorus, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely 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

- -

Aug 03, 2015

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 21, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GAA c.858+7_858+8insAGCGGGC variant involves insertion of 7 nucleotides in an intronic location, which 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 179851/270478 control chromosomes (3918 homozygotes) at a frequency of 0.6649376, which is approximately 158 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The observed allele frequency indicates the variant of interest is the major allele observed in the general population. In addition, the region is indicated to be highly polymorphic in gnomAD. A publication cites the variant to co-occur in an affected individual that carried two pathogenic variants. Furthermore, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Jun 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2015

Mayo Clinic Laboratories, Mayo Clinic

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:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Metabolic myopathy

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 73.16%% (rs3071247, 161447/242952 alleles, 55293 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.1.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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