17-80104538-GCTTTCTT-TCCCTGCTGAGCCTCCTACAGGCCTCCCGC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000152.5(GAA):c.-32-17_-32-10delinsTCCCTGCTGAGCCTCCTACAGGCCTCCCGC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAA NM_000152.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.07

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80104538-GCTTTCTT-TCCCTGCTGAGCCTCCTACAGGCCTCCCGC is Pathogenic according to our data. Variant chr17-80104538-GCTTTCTT-TCCCTGCTGAGCCTCCTACAGGCCTCCCGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1980660.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.-32-17_-32-10delinsTCCCTGCTGAGCCTCCTACAGGCCTCCCGC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.-32-17_-32-10delinsTCCCTGCTGAGCCTCCTACAGGCCTCCCGC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.-32-13T nucleotide in the GAA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2510307, 7881425, 21439876, 22613277, 24245577, 24590251, 26231297). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Pompe disease (PMID: 25037089). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78078337;