rs1042395

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.668G>A (p.Arg223His) in gnomAD v2.1.1 is 0.74034 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92488; 2 star review status) with six submitters classifying the variant as benign, and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145791/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.66 ( 33595 hom., cov: 33)

Exomes 𝑓: 0.71 ( 369171 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:16

Conservation

PhyloP100: -0.0360

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.668G>A	p.Arg223His	missense_variant	Exon 3 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.668G>A	p.Arg223His	missense_variant	Exon 3 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99833

AN:

151982

Hom.:

33582

Cov.:

show subpopulations

Gnomad AFR

AF:

0.536

Gnomad AMI

AF:

0.649

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.770

Gnomad EAS

AF:

0.539

Gnomad SAS

AF:

0.658

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.667

GnomAD3 exomes

AF:

0.666

AC:

162329

AN:

243594

Hom.:

55735

AF XY:

0.681

AC XY:

90323

AN XY:

132592

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.474

Gnomad ASJ exome

AF:

0.779

Gnomad EAS exome

AF:

0.528

Gnomad SAS exome

AF:

0.669

Gnomad FIN exome

AF:

0.752

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.711

AC:

1030164

AN:

1448490

Hom.:

369171

Cov.:

AF XY:

0.712

AC XY:

512807

AN XY:

720028

show subpopulations

Gnomad4 AFR exome

AF:

0.539

Gnomad4 AMR exome

AF:

0.489

Gnomad4 ASJ exome

AF:

0.782

Gnomad4 EAS exome

AF:

0.559

Gnomad4 SAS exome

AF:

0.670

Gnomad4 FIN exome

AF:

0.760

Gnomad4 NFE exome

AF:

0.730

Gnomad4 OTH exome

AF:

0.709

GnomAD4 genome

AF:

0.657

AC:

99875

AN:

152100

Hom.:

33595

Cov.:

AF XY:

0.654

AC XY:

48653

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.536

Gnomad4 AMR

AF:

0.558

Gnomad4 ASJ

AF:

0.770

Gnomad4 EAS

AF:

0.539

Gnomad4 SAS

AF:

0.657

Gnomad4 FIN

AF:

0.775

Gnomad4 NFE

AF:

0.736

Gnomad4 OTH

AF:

0.667

Alfa

AF:

0.713

Hom.:

49456

Bravo

AF:

0.637

TwinsUK

AF:

0.723

AC:

2681

ALSPAC

AF:

0.724

AC:

2792

ESP6500AA

AF:

0.544

AC:

2396

ESP6500EA

AF:

0.738

AC:

6348

ExAC

AF:

0.675

AC:

81893

Asia WGS

AF:

0.580

AC:

2021

AN:

3476

EpiCase

AF:

0.742

EpiControl

AF:

0.742

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:7

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The highest continental population minor allele frequency for c.668G>A (p.Arg223His) in gnomAD v2.1.1 is 0.74034 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92488; 2 star review status) with six submitters classifying the variant as benign, and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -

Feb 18, 2015

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 04, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:3

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.927% in gnomAD_ExomesFounderPop) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype

Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.063

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Uncertain

0.46

T;D;D

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.66

T;.;T

MetaRNN

Benign

0.000017

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

3.3

.;M;M

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.6

.;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.54

.;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.21

.;B;B

Vest4

0.050, 0.049

MPC

0.14

ClinPred

0.033

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.69

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