chr17-80105866-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000152.5(GAA):c.664G>A(p.Val222Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,603,876 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V222V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00025 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00040 ( 10 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.86

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease II
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
glycogen storage disease due to acid maltase deficiency, infantile onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
glycogen storage disease due to acid maltase deficiency, late-onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000152.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.

BP4

Computational evidence support a benign effect (MetaRNN=0.008164853).

BP6

Variant 17-80105866-G-A is Benign according to our data. Variant chr17-80105866-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 290223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 10 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.664G>A	p.Val222Met	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.664G>A	p.Val222Met	missense_variant	Exon 3 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000774

AC:

189

AN:

244194

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000404

AC:

587

AN:

1451558

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

407

AN XY:

721762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.000157

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39620

South Asian (SAS)

AF:

0.00499

AC:

430

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46410

Middle Eastern (MID)

AF:

0.000187

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1109588

Other (OTH)

AF:

0.000565

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000249

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41578

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00498

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000890

AC:

108

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 22, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24627108, 29095812, 23430949, 22644586, 33202836) -

May 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GAA: BS2 -

Glycogen storage disease, type II

Benign:3

Feb 12, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Aug 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GAA c.664G>A (p.Val222Met) results in a conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 244194 control chromosomes, predominantly at a frequency of 0.0054 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.28 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

GAA-related disorder

Benign:1

Mar 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.86

D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.4

.;M;M

PhyloP100

1.9

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.5

.;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.98

.;D;D

Vest4

0.59

MVP

0.95

MPC

0.45

ClinPred

0.096

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.84

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over