17-80107727-A-AGCAGCGG

Position:

• chr17-80107727-A-AGCAGCGG

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 ENST00000302262.8 splice_donor_region, intron
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: 0.160

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 -8 ACMG points.

• BA1: 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.858+7_858+8insAGCGGGC		splice_donor_region_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.858+7_858+8insAGCGGGC		splice_donor_region_variant, intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99093 AN: 151582 Hom.: 33211 Cov.: 0

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

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.: 66 AF XY: 0.711 AC XY: 516049 AN XY: 725774

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.: 0 AF XY: 0.651 AC XY: 48279 AN XY: 74134

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

Submissions by phenotype

Glycogen storage disease, type II Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 19, 2020	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2018	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
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	Genetic Services Laboratory, University of Chicago	Aug 03, 2015	- -

Metabolic myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3071247; hg19: chr17-78081526;