17-80110010-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5c.1392G>C variant in GAA is a missense variant predicted to cause substitution of Arginine by Serine at amino acid 464 (p.Arg464Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (13/128364 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.634 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Another missense variant c.1390A>T, p.Arg464Trp in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 843677). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP. There is a ClinVar entry for this variant (Variation ID: 432217, 1 star review status) with 4 submitters classifying the variant as Uncertain Significance and 1 submitter classifying the variant as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815303/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:6

Conservation

PhyloP100: 0.172

Publications

7 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: PanelApp Australia, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
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 1 ACMG points.

PM2

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	UniProt
GAA	NM_000152.5	MANE Select	c.1392G>C	p.Arg464Ser	missense	Exon 9 of 20	NP_000143.2	P10253
GAA	NM_001079803.3		c.1392G>C	p.Arg464Ser	missense	Exon 10 of 21	NP_001073271.1	P10253
GAA	NM_001079804.3		c.1392G>C	p.Arg464Ser	missense	Exon 9 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAA	ENST00000302262.8	TSL:1 MANE Select	c.1392G>C	p.Arg464Ser	missense	Exon 9 of 20	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.1392G>C	p.Arg464Ser	missense	Exon 10 of 21	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.1392G>C	p.Arg464Ser	missense	Exon 9 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000679

AC:

AN:

250280

AF XY:

0.0000959

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000152

AC:

222

AN:

1460994

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000184

AC:

205

AN:

1111880

Other (OTH)

AF:

0.000199

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.0000985

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

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:

0.000113

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

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 (5)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

-0.030

MutationAssessor

Uncertain

2.0

PhyloP100

0.17

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.63

Sift

Benign

0.12

Sift4G

Benign

0.45

Polyphen

0.90

Vest4

0.89

MutPred

0.58

Gain of glycosylation at R464 (P = 0.0224)

MVP

0.98

MPC

0.46

ClinPred

0.50

GERP RS

-2.1

Varity_R

0.78

gMVP

0.85

Mutation Taster

=46/54

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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