rs201056962

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000152.5(GAA):c.858G>A(p.Thr286Thr) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000133 in 1,349,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GAA
NM_000152.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9997

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 5.18

Publications

5 publications found

Variant links:

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

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-80107722-G-A is Pathogenic according to our data. Variant chr17-80107722-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 572952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.858G>A	p.Thr286Thr	splice_region_variant, synonymous_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.858G>A	p.Thr286Thr	splice_region_variant, synonymous_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00000915

AC:

AN:

109332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000207

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000209

AC:

AN:

143204

AF XY:

0.00

show subpopulations

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:

0.0000489

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1239742

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

614208

show subpopulations

African (AFR)

AF:

0.0000669

AC:

AN:

29880

American (AMR)

AF:

0.0000264

AC:

AN:

37900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20462

East Asian (EAS)

AF:

0.00

AC:

AN:

35978

South Asian (SAS)

AF:

0.0000279

AC:

AN:

71662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

0.0000116

AC:

AN:

945314

Other (OTH)

AF:

0.0000197

AC:

AN:

50884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000914

AC:

AN:

109426

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

52600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31656

American (AMR)

AF:

0.00

AC:

AN:

11554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2446

East Asian (EAS)

AF:

0.00

AC:

AN:

4046

South Asian (SAS)

AF:

0.00

AC:

AN:

3222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

48186

Other (OTH)

AF:

0.00

AC:

AN:

1416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:2Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 286 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201056962, gnomAD 0.003%). This variant has been observed in individual(s) with late-onset Pompe disease (PMID: 35123877). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 572952). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

5.2

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.62

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over