rs1126690

Positions:

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.2338G>A (p.Val780Ile) in gnomAD v2.1.1 is 0.8129 in the South Asian 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: 92476; 2 star review status) with six submitters classifying the variant as 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/CA145769/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.72 ( 39719 hom., cov: 32)

Exomes 𝑓: 0.74 ( 404210 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:14

Conservation

PhyloP100: -1.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2338G>A	p.Val780Ile	missense_variant	17/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2338G>A	p.Val780Ile	missense_variant	17/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.720

AC:

109406

AN:

151932

Hom.:

39700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.695

Gnomad AMI

AF:

0.648

Gnomad AMR

AF:

0.579

Gnomad ASJ

AF:

0.789

Gnomad EAS

AF:

0.628

Gnomad SAS

AF:

0.810

Gnomad FIN

AF:

0.809

Gnomad MID

AF:

0.851

Gnomad NFE

AF:

0.751

Gnomad OTH

AF:

0.711

GnomAD3 exomes

AF:

0.717

AC:

178198

AN:

248394

Hom.:

65599

AF XY:

0.733

AC XY:

98865

AN XY:

134816

show subpopulations

Gnomad AFR exome

AF:

0.696

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.800

Gnomad EAS exome

AF:

0.619

Gnomad SAS exome

AF:

0.813

Gnomad FIN exome

AF:

0.797

Gnomad NFE exome

AF:

0.757

Gnomad OTH exome

AF:

0.753

GnomAD4 exome

AF:

0.742

AC:

1083650

AN:

1460334

Hom.:

404210

Cov.:

AF XY:

0.746

AC XY:

541672

AN XY:

726500

show subpopulations

Gnomad4 AFR exome

AF:

0.699

Gnomad4 AMR exome

AF:

0.501

Gnomad4 ASJ exome

AF:

0.802

Gnomad4 EAS exome

AF:

0.672

Gnomad4 SAS exome

AF:

0.808

Gnomad4 FIN exome

AF:

0.798

Gnomad4 NFE exome

AF:

0.746

Gnomad4 OTH exome

AF:

0.749

GnomAD4 genome

AF:

0.720

AC:

109467

AN:

152050

Hom.:

39719

Cov.:

AF XY:

0.719

AC XY:

53428

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.695

Gnomad4 AMR

AF:

0.578

Gnomad4 ASJ

AF:

0.789

Gnomad4 EAS

AF:

0.628

Gnomad4 SAS

AF:

0.809

Gnomad4 FIN

AF:

0.809

Gnomad4 NFE

AF:

0.751

Gnomad4 OTH

AF:

0.712

Alfa

AF:

0.743

Hom.:

64764

Bravo

AF:

0.701

TwinsUK

AF:

0.742

AC:

2751

ALSPAC

AF:

0.742

AC:

2858

ESP6500AA

AF:

0.701

AC:

3087

ESP6500EA

AF:

0.750

AC:

6446

ExAC

AF:

0.728

AC:

88350

Asia WGS

AF:

0.723

AC:

2517

AN:

3478

EpiCase

AF:

0.754

EpiControl

AF:

0.756

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 23, 2020	The highest continental population minor allele frequency for c.2338G>A (p.Val780Ile) in gnomAD v2.1.1 is 0.8129 in the South Asian 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: 92476; 2 star review status) with six submitters classifying the variant as 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 81.682% in ExAC) 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.7 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -

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

0.078

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.2

DANN

Benign

0.65

DEOGEN2

Uncertain

0.46

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.18

.;T

MetaRNN

Benign

0.0000010

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.16

Sift

Benign

0.59

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.0010

B;B

Vest4

0.043

MPC

0.088

ClinPred

0.00059

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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