chr17-80112716-G-T

Variant names:

• chr17-80112716-G-T
• rs528282884
• NM_000152.5:c.1888+5G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1888+5G>T variant alters the donor splice site consensus sequence of intron 13 in GAA. GAA activity is available for 3 patients with this variant (PMID:33202836; clinical diagnostic laboratories). Although all of these patients have been reported to have reduced GAA activity, they are all heterozygous for the c.2065G>A (p.Glu689Lys) pseudodeficiency variant. These patients were either identified as "suspected" late onset Pompe disease by newborn screen (PMID:33202836, clinical laboratory), or no further clinical information is available (clinical laboratories). Without confirmation that the variant has been found in a patient with characteristics of Pompe disease, other than reduced GAA activity that could be attributed to pseudodeficiency, PP4 is not met at the current time. All 3 patients with documented GAA deficiency are compound heterozygous for the variant along with c.2065G>A (p.Glu689Lys), and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.-32-13T>G (ClinVar Variation ID: 4027) (with c.510C>T, which is believed to be a modifier, typically occurring in cis with c.-32-13T>G), c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) (PMID:33202836, clinical laboratory), and c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1). However, because PP4 was not met, and it is unclear if these patients have Pompe disease, PM3 is not met at any weight at the current time. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006 (2/33202 alleles) in the Latino population and, in gnomAD v4.1, the highest population MAF is 0.0004094 (24/58624 alleles) in the Admixed American population both of which are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, results from RNA studies on this variant are not available. SpliceAI indicates that the variant has no significant impact on splicing (donor loss score= 0.04; acceptor gain 126 bp downstream, score 0.11=, donor gain 83 bp downstream, score=0.13) (BP4). There is a ClinVar entry for this variant (Variation ID: 283971). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM2_Supporting, BP4(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815512/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Uncertain significance reviewed by expert panel U:9
• Conservation: PhyloP100: 3.69
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.1888+5G>T		splice_region intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1888+5G>T		splice_region intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1888+5G>T		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.1888+5G>T		splice_region intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1888+5G>T		splice_region intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1903+5G>T		splice_region intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 224656 AF XY: 0.00000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000618

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.00000757 AC: 11 AN: 1452246 Hom.: 0 Cov.: 33 AF XY: 0.00000831 AC XY: 6 AN XY: 721816

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.0000693 AC: 3 AN: 43314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 84890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108268

Other (OTH) AF: 0.000117 AC: 7 AN: 60010

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74472

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.00137 AC: 21 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.000317

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	-	Glycogen storage disease, type II (4)
-	3	-	not provided (3)
-	1	-	GAA-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.55
PhyloP100		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.040		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: rs528282884; hg19: chr17-78086515;