rs12452721

Positions:

• chr17-80105710-T-G

Variant summary

Our verdict is Benign. Variant got -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:8
• Conservation: PhyloP100: -0.535

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 255363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80105710-T-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
GAA	NM_000152.5	c.547-39T>G		intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.547-39T>G		intron_variant		1	NM_000152.5	P1

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

GnomAD3 exomes AF: 0.668 AC: 164713 AN: 246584 Hom.: 56633 AF XY: 0.683 AC XY: 91427 AN XY: 133854

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 SAS exome AF: 0.677

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

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.761

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.711

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

Gnomad4 AFR AF: 0.537

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.668

Alfa AF: 0.712 Hom.: 7143

Bravo AF: 0.638

Asia WGS AF: 0.588 AC: 2049 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2017	- -

Glycogen storage disease, type II Benign:3

Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2018

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

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