rs12452721

Variant names:

• chr17-80105710-T-G
• rs12452721
• NM_000152.5:c.547-39T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.547-39T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,603,762 control chromosomes in the GnomAD database, including 405,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33614 hom., cov: 31)
  • Exomes 𝑓: 0.71 (371596 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.535
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-80105710-T-G is Benign according to our data. Variant chr17-80105710-T-G is described in ClinVar as Benign. ClinVar VariationId is 255363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.547-39T>G		intron_variant	Intron 2 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.547-39T>G		intron_variant	Intron 2 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99838 AN: 151858 Hom.: 33601 Cov.: 31

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.669

GnomAD2 exomes AF: 0.668 AC: 164713 AN: 246584 AF XY: 0.683

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.712 AC: 1034169 AN: 1451786 Hom.: 371596 Cov.: 35 AF XY: 0.713 AC XY: 515518 AN XY: 722568

African (AFR) AF: 0.540 AC: 17996 AN: 33332

American (AMR) AF: 0.489 AC: 21842 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20416 AN: 26098

East Asian (EAS) AF: 0.560 AC: 22188 AN: 39652

South Asian (SAS) AF: 0.677 AC: 58264 AN: 86118

European-Finnish (FIN) AF: 0.761 AC: 37501 AN: 49294

Middle Eastern (MID) AF: 0.797 AC: 4536 AN: 5690

European-Non Finnish (NFE) AF: 0.731 AC: 808685 AN: 1106794

Other (OTH) AF: 0.711 AC: 42741 AN: 60138

GnomAD4 genome AF: 0.657 AC: 99881 AN: 151976 Hom.: 33614 Cov.: 31 AF XY: 0.655 AC XY: 48634 AN XY: 74264

African (AFR) AF: 0.537 AC: 22246 AN: 41416

American (AMR) AF: 0.558 AC: 8524 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2672 AN: 3468

East Asian (EAS) AF: 0.539 AC: 2783 AN: 5160

South Asian (SAS) AF: 0.664 AC: 3201 AN: 4822

European-Finnish (FIN) AF: 0.775 AC: 8188 AN: 10564

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50016 AN: 67958

Other (OTH) AF: 0.668 AC: 1409 AN: 2108

Alfa AF: 0.707 Hom.: 7247

Bravo AF: 0.638

Asia WGS AF: 0.588 AC: 2049 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

- -

Aug 07, 2017

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:3

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

The c.547-39T>G variant in GAA has been reported in at least 6 individuals with suspected glycogen storage disease II (PMID: 28032299, 25681614), and has also been reported in ClinVar (VariationID: 255363) as benign by EGL Genetic Diagnostics and PreventionGenetics. This variant has been identified in 77.9% (8028/10312) of Ashkenazi Jewish chromosomes, including 3120 homozygotes, and is present at high frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12452721). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for glycogen storage disease II in an autosomal recessive manner based on high frequency in the general population. ACMG/AMP Criteria applied: BA1, BP7, BP4 (Richards 2015). -

not provided Benign:2

Dec 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30595407, 24008937, 25681614, 28032299) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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: rs12452721; hg19: chr17-78079509; COSMIC: COSV56408692; COSMIC: COSV56408692;