rs796051877

Variant names:

• chr17-80110055-G-A
• rs796051877
• NM_000152.5:c.1437G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80110055-G-A
• chr17-80110055-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000152.5(GAA):​c.1437G>A​(p.Lys479Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000685 in 1,459,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.20
• Publications: 7 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-80110055-G-A is Pathogenic according to our data. Variant chr17-80110055-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 188044.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1437G>A	p.Lys479Lys	splice_region_variant, synonymous_variant	Exon 9 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1437G>A	p.Lys479Lys	splice_region_variant, synonymous_variant	Exon 9 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248208 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459802 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110880

Other (OTH) AF: 0.00 AC: 0 AN: 60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.1437G>A (p.Lys479=) variant in GAA has been reported in 4 individuals (including 1 from the UK, 1 Guatemalan, and 1 Arabic individuals) with Glycogen Storage Disease II (PMID: 26873529, 18425781, 25243733, 26160551), and has also been reported pathogenic by the Freeman-Sheldon Research Group (deGruyter-McKusick Institute of Health Sciences) in ClinVar based on a case family (Variation ID: 188044). This variant has been identified in 0.003% (1/30606) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs796051877). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the c.1437G>A variant may impact GAA expression and splicing (PMID: 18425781, 25243733). However, these types of assays may not accurately represent biological function. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in an individual with Glycogen Storage Disease II increases the likelihood that the c.1437G>A variant is pathogenic (PMID: 25243733). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in their fibroblasts (PMID: 25243733). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PP3, PP4, PM2, PS3_Supporting (Richards 2015). -

Dec 21, 2014

Freeman-Sheldon Research Group, deGruyter-McKusick Institute of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.88
PhyloP100		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 0

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

Other links and lift over

dbSNP: rs796051877; hg19: chr17-78083854;