rs1278892703

Positions:

• chr17-80104676-CCTA-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2_Supporting BP4 PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.93_95del variant in GAA is predicted to cause a change in the length of the protein (p.Leu32del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001149 (1/8700 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. PROVEAN and Mutation Taster predict that the variant will have no impact on GAA function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 526535). 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 (Specifications Version 2.0): PM2_Supporting, PM4_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 28, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA628018663/MONDO:0009290/010

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GAA NM_000152.5 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 2.54

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.93_95del	p.Leu32del	inframe_deletion	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.93_95del	p.Leu32del	inframe_deletion	2/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 28, 2023	The NM_000152.5:c.93_95del variant in GAA is predicted to cause a change in the length of the protein (p.Leu32del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001149 (1/8700 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. PROVEAN and Mutation Taster predict that the variant will have no impact on GAA function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 526535). 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 (Specifications Version 2.0): PM2_Supporting, PM4_Supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 28, 2023) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 23, 2022	ClinVar contains an entry for this variant (Variation ID: 526535). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant, c.93_95del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Leu32del), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1278892703; hg19: chr17-78078475;