17-80118674-G-C

Position:

chr17-80118674-G-C

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2668G>C variant in GAA is predicted to result in the missense substitution of valine by leucine at amino acid position 890. The highest population minor allele frequency in gnomAD v2.1.1 is 0.02652 (812/30616 alleles with 13 homozygotes) in the South Asian population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 255361). In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BA1.(Classified approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815831/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 40 hom. )

Consequence

GAA
ENST00000302262.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: 0.0280

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2668G>C	p.Val890Leu	missense_variant	19/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2668G>C	p.Val890Leu	missense_variant	19/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00338

AC:

845

AN:

250280

Hom.:

AF XY:

0.00429

AC XY:

581

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.0265

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00168

AC:

2451

AN:

1460462

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

1699

AN XY:

726506

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0264

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.000873

AC:

133

AN:

152306

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0265

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000239

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00364

AC:

442

Asia WGS

AF:

0.0150

AC:

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:7

Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Val890Leu variant in GAA has been reported as a benign variant (by GeneDx, Invitae, EGL, and Prevention Genetics) and a VUS (by Illumina) in ClinVar (Variation ID: 255361). This variant has been identified in 2.652% (812/30616) of South Asian chromosomes, including 13 homozygotes, as well as other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377286472). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. 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, BP4 (Richards 2015). -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 01, 2023	The NM_000152.5:c.2668G>C variant in GAA is predicted to result in the missense substitution of valine by leucine at amino acid position 890. The highest population minor allele frequency in gnomAD v2.1.1 is 0.02652 (812/30616 alleles with 13 homozygotes) in the South Asian population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 255361). In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BA1. (Classified approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 24, 2019	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2015	- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Nov 14, 2017

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2023

This alteration is classified as likely 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

0.084

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.5

DANN

Benign

0.25

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.65

.;T

MetaRNN

Benign

0.0076

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.85

L;L

MutationTaster

Benign

0.71

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

0.23

N;N

REVEL

Benign

0.18

Sift

Benign

0.59

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.0

B;B

Vest4

0.053

MutPred

0.42

Gain of catalytic residue at V890 (P = 5e-04);Gain of catalytic residue at V890 (P = 5e-04);

MVP

0.85

MPC

0.11

ClinPred

0.0019

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.071

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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