rs1800309

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000152.5(GAA):c.2065G>A(p.Glu689Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,601,260 control chromosomes in the GnomAD database, including 2,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★).

Frequency

Genomes: 𝑓 0.044 ( 308 hom., cov: 34)

Exomes 𝑓: 0.046 ( 2661 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts P:1B:13O:2

Conservation

PhyloP100: 2.05

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 links:

GAA (HGNC:):

GAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a helix (size 15) in uniprot entity LYAG_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000152.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0015834868).

BP6

Variant 17-80113242-G-A is Benign according to our data. Variant chr17-80113242-G-A is described in ClinVar as [Benign, other]. Clinvar id is 4030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80113242-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2065G>A	p.Glu689Lys	missense_variant	15/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2065G>A	p.Glu689Lys	missense_variant	15/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0437

AC:

6657

AN:

152194

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0391

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.238

Gnomad SAS

AF:

0.0689

Gnomad FIN

AF:

0.0653

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0396

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0556

AC:

12525

AN:

225448

Hom.:

689

AF XY:

0.0556

AC XY:

6795

AN XY:

122174

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.0259

Gnomad ASJ exome

AF:

0.0409

Gnomad EAS exome

AF:

0.234

Gnomad SAS exome

AF:

0.0624

Gnomad FIN exome

AF:

0.0621

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0573

GnomAD4 exome

AF:

0.0457

AC:

66223

AN:

1448948

Hom.:

2661

Cov.:

AF XY:

0.0463

AC XY:

33325

AN XY:

719752

show subpopulations

Gnomad4 AFR exome

AF:

0.0195

Gnomad4 AMR exome

AF:

0.0272

Gnomad4 ASJ exome

AF:

0.0427

Gnomad4 EAS exome

AF:

0.257

Gnomad4 SAS exome

AF:

0.0612

Gnomad4 FIN exome

AF:

0.0670

Gnomad4 NFE exome

AF:

0.0374

Gnomad4 OTH exome

AF:

0.0522

GnomAD4 genome

AF:

0.0438

AC:

6671

AN:

152312

Hom.:

308

Cov.:

AF XY:

0.0456

AC XY:

3396

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0205

Gnomad4 AMR

AF:

0.0389

Gnomad4 ASJ

AF:

0.0409

Gnomad4 EAS

AF:

0.238

Gnomad4 SAS

AF:

0.0691

Gnomad4 FIN

AF:

0.0653

Gnomad4 NFE

AF:

0.0396

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0471

Hom.:

270

Bravo

AF:

0.0399

TwinsUK

AF:

0.0326

AC:

121

ALSPAC

AF:

0.0337

AC:

130

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.0348

AC:

299

ExAC

AF:

0.0515

AC:

6210

Asia WGS

AF:

0.149

AC:

520

AN:

3478

ClinVar

Significance: Benign; other

Submissions summary: Pathogenic:1Benign:13Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu689Lys variant in GAA has been reported as a benign and likely benign variant for Glycogen Storage Disease II in ClinVar (Variation ID: 4030). This variant has been identified in 5.490% (13805/251476) of chromosomes, including 757 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800309). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. It is a known pseudodeficiency allele that causes false-positive results in GAA deficiency enzyme assays (PMID: 20080426, 18301443). In summary, this variant meets criteria to be classified as benign for Glycogen Storage Disease II in an autosomal recessive manner based on its frequency in the general population. ACMG/AMP Criteria applied: BA1 (Richards 2015). -
other, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2019	- pseudodeficiency allele
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant reported in multiple Invitae PIN participants. Variant interpreted as Benign (Pseudo deficiency allele) most recently on 9/29/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

Acid alpha-glucosidase, allele 4

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Sep 01, 1996

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.60

D;D

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.58

.;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.16

Sift

Benign

0.35

T;T

Sift4G

Benign

0.67

T;T

Polyphen

0.092

B;B

Vest4

0.080

MPC

0.14

ClinPred

0.0035

GERP RS

1.5

Varity_R

0.086

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over