17-80107727-A-AGCAGCGG

Variant names:

• chr17-80107727-A-AGCAGCGG
• rs3071247
• NM_000152.5:c.858+7_858+8insAGCGGGC

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.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 NM_000152.5 splice_region, intron
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 0.160
• Publications: 6 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.858+7_858+8insAGCGGGC		splice_region intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.858+7_858+8insAGCGGGC		splice_region intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.858+7_858+8insAGCGGGC		splice_region intron	N/A	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.858+5_858+6insGCAGCGG		splice_region intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.858+5_858+6insGCAGCGG		splice_region intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.858+5_858+6insGCAGCGG		splice_region intron	N/A	ENSP00000603465.1

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

GnomAD2 exomes AF: 0.665 AC: 161447 AN: 242952 AF XY: 0.679

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 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

African (AFR) AF: 0.531 AC: 17770 AN: 33446

American (AMR) AF: 0.486 AC: 21709 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20376 AN: 26064

East Asian (EAS) AF: 0.558 AC: 22131 AN: 39656

South Asian (SAS) AF: 0.664 AC: 57193 AN: 86168

European-Finnish (FIN) AF: 0.765 AC: 39858 AN: 52122

Middle Eastern (MID) AF: 0.795 AC: 4577 AN: 5760

European-Non Finnish (NFE) AF: 0.729 AC: 809947 AN: 1110886

Other (OTH) AF: 0.708 AC: 42659 AN: 60276

GnomAD4 genome AF: 0.654 AC: 99137 AN: 151700 Hom.: 33224 Cov.: 0 AF XY: 0.651 AC XY: 48279 AN XY: 74134

African (AFR) AF: 0.529 AC: 21914 AN: 41406

American (AMR) AF: 0.555 AC: 8462 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2660 AN: 3458

East Asian (EAS) AF: 0.537 AC: 2757 AN: 5132

South Asian (SAS) AF: 0.651 AC: 3127 AN: 4806

European-Finnish (FIN) AF: 0.775 AC: 8202 AN: 10582

Middle Eastern (MID) AF: 0.844 AC: 238 AN: 282

European-Non Finnish (NFE) AF: 0.735 AC: 49797 AN: 67774

Other (OTH) AF: 0.665 AC: 1398 AN: 2102

Alfa AF: 0.672 Hom.: 3729

EpiCase AF: 0.741

EpiControl AF: 0.735

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Metabolic myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3071247; hg19: chr17-78081526; COSMIC: COSV100163325; COSMIC: COSV100163325;