rs142626724

Variant names:

• chr17-80107716-G-A
• rs142626724
• NM_000152.5:c.852G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107716-G-A
• chr17-80107716-G-T

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.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 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/CA198776/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0062 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0084 (72 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: -0.377
• Publications: 9 publications found

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

ACMG classification

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	c.852G>A	p.Ala284Ala	synonymous_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.852G>A	p.Ala284Ala	synonymous_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 895 AN: 142998 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00920

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00927

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00204

Gnomad FIN AF: 0.00266

Gnomad MID AF: 0.0199

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00629 AC: 1563 AN: 248578 AF XY: 0.00650

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00775

GnomAD4 exome AF: 0.00840 AC: 12263 AN: 1460388 Hom.: 72 Cov.: 34 AF XY: 0.00830 AC XY: 6033 AN XY: 726540

African (AFR) AF: 0.00176 AC: 59 AN: 33466

American (AMR) AF: 0.00494 AC: 221 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00701 AC: 183 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86246

European-Finnish (FIN) AF: 0.00308 AC: 161 AN: 52312

Middle Eastern (MID) AF: 0.0219 AC: 126 AN: 5766

European-Non Finnish (NFE) AF: 0.00972 AC: 10811 AN: 1111736

Other (OTH) AF: 0.00824 AC: 497 AN: 60346

GnomAD4 genome AF: 0.00624 AC: 893 AN: 143118 Hom.: 2 Cov.: 34 AF XY: 0.00581 AC XY: 404 AN XY: 69592

African (AFR) AF: 0.00161 AC: 63 AN: 39030

American (AMR) AF: 0.00594 AC: 85 AN: 14302

Ashkenazi Jewish (ASJ) AF: 0.00927 AC: 31 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4906

South Asian (SAS) AF: 0.00204 AC: 9 AN: 4408

European-Finnish (FIN) AF: 0.00266 AC: 25 AN: 9406

Middle Eastern (MID) AF: 0.0179 AC: 5 AN: 280

European-Non Finnish (NFE) AF: 0.0100 AC: 647 AN: 64660

Other (OTH) AF: 0.0105 AC: 20 AN: 1912

Alfa AF: 0.00767 Hom.: 1

Bravo AF: 0.00629

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 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. -

not specified Benign:4

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 22, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.852G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0063 in 248578 control chromosomes, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.852G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) without strong evidence of causality (Gort_2007, Herzog_2012, Kroos_2008) . These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

not provided Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAA: BP4, BP7, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 30, 2016

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

Jun 10, 2021

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	-0.69
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		-0.38
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs142626724; hg19: chr17-78081515;