Variant NM_000152.5:c.858+7_858+8insAGCGGGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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:16

Conservation

PhyloP100: 0.160

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.665

AC:

161447

AN:

242952

Hom.:

55293

AF XY:

0.679

AC XY:

90037

AN XY:

132662

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 SAS exome

AF:

0.665

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

Gnomad4 AFR exome

AF:

0.531

Gnomad4 AMR exome

AF:

0.486

Gnomad4 ASJ exome

AF:

0.782

Gnomad4 EAS exome

AF:

0.558

Gnomad4 SAS exome

AF:

0.664

Gnomad4 FIN exome

AF:

0.765

Gnomad4 NFE exome

AF:

0.729

Gnomad4 OTH exome

AF:

0.708

GnomAD4 genome

AF:

0.654

AC:

99137

AN:

151700

Hom.:

33224

Cov.:

AF XY:

0.651

AC XY:

48279

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.529

Gnomad4 AMR

AF:

0.555

Gnomad4 ASJ

AF:

0.769

Gnomad4 EAS

AF:

0.537

Gnomad4 SAS

AF:

0.651

Gnomad4 FIN

AF:

0.775

Gnomad4 NFE

AF:

0.735

Gnomad4 OTH

AF:

0.665

Alfa

AF:

0.672

Hom.:

3729

EpiCase

AF:

0.741

EpiControl

AF:

0.735

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

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. -

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

- -

not provided

Benign:5

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. -

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

Significance: Likely 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

- -

Dec 07, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

Sep 04, 2018

Eurofins Ntd Llc (ga)

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

- -

Aug 03, 2015

Genetic Services Laboratory, University of Chicago

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

- -

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

Splicing

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