rs372799904

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4BP6

The NM_000152.5(GAA):c.1232G>A(p.Arg411Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R411W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.411

Publications

6 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 1 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000152.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.

BP4

Computational evidence support a benign effect (MetaRNN=0.35700032).

BP6

Variant 17-80108734-G-A is Benign according to our data. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459. Variant chr17-80108734-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 657459.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 8 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.1232G>A	p.Arg411Gln	missense_variant	Exon 8 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000525

AC:

AN:

247666

AF XY:

0.0000594

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460056

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726290

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111742

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000158

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000225

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000743

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Uncertain:2Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

May 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19343043, 22253258) -

May 29, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GAA-related disorder

Uncertain:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GAA c.1232G>A variant is predicted to result in the amino acid substitution p.Arg411Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.049% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;D

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.066

LIST_S2

Uncertain

0.87

.;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.41

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.24

Sift

Benign

0.26

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.045

B;B

Vest4

0.38

MVP

0.95

MPC

0.14

ClinPred

0.020

GERP RS

0.25

Varity_R

0.30

gMVP

0.70

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over