rs111261964

Variant names:

• chr17-80110928-G-A
• rs111261964
• NM_000152.5:c.1552-13G>A

Variant summary

Our verdict is Likely benign. The variant received -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 intron
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:12
• Conservation: PhyloP100: -0.245
• Publications: 0 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -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.

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.1552-13G>A		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1552-13G>A		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1552-13G>A		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.1552-13G>A		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1552-13G>A		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1567-13G>A		intron	N/A	ENSP00000603465.1

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

GnomAD2 exomes AF: 0.00278 AC: 698 AN: 251278 AF XY: 0.00280

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 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

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.00183 AC: 82 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86258

European-Finnish (FIN) AF: 0.000976 AC: 52 AN: 53262

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00530 AC: 5898 AN: 1111894

Other (OTH) AF: 0.00432 AC: 261 AN: 60390

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

African (AFR) AF: 0.00101 AC: 42 AN: 41560

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00466 AC: 317 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00381 Hom.: 1

Bravo AF: 0.00283

Asia WGS AF: 0.00173 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	Glycogen storage disease, type II (5)
-	1	4	not provided (5)
-	-	4	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.63
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111261964; hg19: chr17-78084727;