rs111261964

Positions:

• chr17-80110928-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1552-13G>A variant is located near the acceptor splice region of intron 10 of GAA. The computational splicing predictor SpliceAI predicts that the variant has no impact on splicing (BP4). To our knowledge, functional studies investigating the impact of this variant on splicing are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004705 (607/129008 alleles) in the European non-Finnish population, which meets the ClinGen LSD VCEP’s threshold for BS1 (>0.005) when rounded up (BS1). There are 2 homozygotes in gnomAD v2.1.1. The variant was reported in a patient with Pompe disease along with a variant that has been classified as pathogenic by the ClinGen LD VCEP (c.841C>T (p.Arg281Trp); the phase was not reported in that patient (PMID:31086307). However, analysis of clinical laboratory data in multiple patients with these two variants indicates that they likely occur in cis. There is a ClinVar entry for this variant (Variation ID: 255353). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BS1, BP4.Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 18th, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815382/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (19 hom.)
• Consequence: GAA NM_000152.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:11
• Conservation: PhyloP100: -0.245

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 Likely_benign. Variant got -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1552-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1552-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152162 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00278 AC: 698 AN: 251278 Hom.: 2 AF XY: 0.00280 AC XY: 381 AN XY: 135866

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00443 AC: 6474 AN: 1461588 Hom.: 19 Cov.: 36 AF XY: 0.00439 AC XY: 3189 AN XY: 727092

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.000976

Gnomad4 NFE exome AF: 0.00530

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152280 Hom.: 1 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74444

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00466

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00458 Hom.: 1

Bravo AF: 0.00283

Asia WGS AF: 0.00173 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.1552-13G>A variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a likely benign variant (by GeneDx, EGL, and Prevention Genetics) and as a VUS (by Illumina) in ClinVar (Variation ID: 255353). This variant has been identified in 0.4705% (607/129008) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111261964). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (PMID: 25741868). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 18, 2023	The NM_000152.5:c.1552-13G>A variant is located near the acceptor splice region of intron 10 of GAA. The computational splicing predictor SpliceAI predicts that the variant has no impact on splicing (BP4). To our knowledge, functional studies investigating the impact of this variant on splicing are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004705 (607/129008 alleles) in the European non-Finnish population, which meets the ClinGen LSD VCEP’s threshold for BS1 (>0.005) when rounded up (BS1). There are 2 homozygotes in gnomAD v2.1.1. The variant was reported in a patient with Pompe disease along with a variant that has been classified as pathogenic by the ClinGen LD VCEP (c.841C>T (p.Arg281Trp); the phase was not reported in that patient (PMID: 31086307). However, analysis of clinical laboratory data in multiple patients with these two variants indicates that they likely occur in cis. There is a ClinVar entry for this variant (Variation ID: 255353). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BS1, BP4. Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 18th, 2023). -

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GAA: BS2 -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 17, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2018	Variant summary: The GAA c.1552-13G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 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 788/277130 control chromosomes (2 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.004675 (592/126628)(gnomAD). This frequency is slightly above the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign and one other lab classified it as VUS. Taken together, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111261964; hg19: chr17-78084727;