rs535644999

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2_SupportingPM3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 4 patients have been identified with this variant. Two had documented GAA deficiency, one with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID:21757382; 18458862) and one within affected range in dried blood spot (Clinical diagnostic laboratory). (PP4_Moderate). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3). Additional patients had evidence of pseudodeficiency variants with (PMID:21484825, 28302345). The computational predictor REVEL gives a score of 0.531 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 188480). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_Moderate, PM3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA198786/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:9

Conservation

PhyloP100: 6.13

Publications

11 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	NM_000152.5	MANE Select	c.1375G>A	p.Asp459Asn	missense	Exon 9 of 20	NP_000143.2
GAA	NM_001079803.3		c.1375G>A	p.Asp459Asn	missense	Exon 10 of 21	NP_001073271.1
GAA	NM_001079804.3		c.1375G>A	p.Asp459Asn	missense	Exon 9 of 20	NP_001073272.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	ENST00000302262.8	TSL:1 MANE Select	c.1375G>A	p.Asp459Asn	missense	Exon 9 of 20	ENSP00000305692.3
GAA	ENST00000390015.7	TSL:1	c.1375G>A	p.Asp459Asn	missense	Exon 10 of 21	ENSP00000374665.3
GAA	ENST00000933406.1		c.1375G>A	p.Asp459Asn	missense	Exon 9 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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:

0.0000719

AC:

AN:

250268

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1460938

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000358

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52666

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111874

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000197

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74520

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41594

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000416442), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (9)

not provided (3)

Acute rhabdomyolysis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.2

PhyloP100

6.1

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.53

Sift

Benign

0.040

Sift4G

Uncertain

0.055

Polyphen

0.99

Vest4

0.89

MutPred

0.81

Loss of phosphorylation at Y455 (P = 0.1131)

MVP

1.0

MPC

0.51

ClinPred

0.87

GERP RS

5.4

Varity_R

0.70

gMVP

0.79

Mutation Taster

=10/90

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over