rs1042395

Variant summary

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

The NM_000152.5(GAA):c.668G>A(p.Arg223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,600,590 control chromosomes in the GnomAD database, including 402,766 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223C) has been classified as Uncertain significance.

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:15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_000152.5

BP4

Computational evidence support a benign effect (MetaRNN=1.7431934E-5).

BP6

Variant 17-80105870-G-A is Benign according to our data. Variant chr17-80105870-G-A is described in ClinVar as [Benign]. Clinvar id is 92488.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80105870-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.668G>A	p.Arg223His	missense_variant	3/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.668G>A	p.Arg223His	missense_variant	3/20	1	NM_000152.5	P1

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:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:7

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 22, 2020	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 18, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -

not provided

Uncertain:1Benign:2

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	- -
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: 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. -

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

0.063

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

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.35

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