rs1800314

Positions:

chr17-80117714-G-A

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.2446G>A (p.Val816Ile) in gnomAD v2.1.1 is 0.14249 in the African 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: 92477; 2 star review status) with four submitters classifying the variant as benign, and two 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/CA145772/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.059 ( 537 hom., cov: 33)

Exomes 𝑓: 0.029 ( 1912 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -0.268

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.2446G>A	p.Val816Ile	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.2446G>A	p.Val816Ile	missense_variant	17/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0593

AC:

9013

AN:

152116

Hom.:

536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.0985

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.0354

GnomAD3 exomes

AF:

0.0497

AC:

12170

AN:

244638

Hom.:

628

AF XY:

0.0509

AC XY:

6773

AN XY:

133190

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.0940

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.0333

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0320

GnomAD4 exome

AF:

0.0295

AC:

43026

AN:

1459440

Hom.:

1912

Cov.:

AF XY:

0.0320

AC XY:

23214

AN XY:

725992

show subpopulations

Gnomad4 AFR exome

AF:

0.145

Gnomad4 AMR exome

AF:

0.0345

Gnomad4 ASJ exome

AF:

0.0198

Gnomad4 EAS exome

AF:

0.117

Gnomad4 SAS exome

AF:

0.136

Gnomad4 FIN exome

AF:

0.0322

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0373

GnomAD4 genome

AF:

0.0593

AC:

9032

AN:

152234

Hom.:

537

Cov.:

AF XY:

0.0610

AC XY:

4539

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.143

Gnomad4 AMR

AF:

0.0277

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.0983

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.0334

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.0360

Alfa

AF:

0.0253

Hom.:

Bravo

AF:

0.0597

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.141

AC:

622

ESP6500EA

AF:

0.00989

AC:

ExAC

AF:

0.0530

AC:

6427

Asia WGS

AF:

0.140

AC:

485

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

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.2446G>A (p.Val816Ile) in gnomAD v2.1.1 is 0.14249 in the African 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: 92477; 2 star review status) with four submitters classifying the variant as benign, and two 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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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)	Aug 13, 2013	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 1684505, 25681614, 25526786, 17210890, 8486380, 8094613) -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2019

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

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.8

DANN

Benign

0.89

DEOGEN2

Uncertain

0.54

D;D

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.89

L;L

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

0.31

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.16

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0080

B;B

Vest4

0.033

MPC

0.11

ClinPred

0.0097

GERP RS

-9.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.50

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