Genetic Variant GAA:p.Ala719Ser (chr17-80113332-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBP6

The NM_000152.5(GAA):c.2155G>T(p.Ala719Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,595,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A719E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: -1.95

Publications

8 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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=0.042203188).

BP6

Variant 17-80113332-G-T is Benign according to our data. Variant chr17-80113332-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286435.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAA	NM_000152.5	MANE Select	c.2155G>T	p.Ala719Ser	missense	Exon 15 of 20	NP_000143.2	P10253
GAA	NM_001079803.3		c.2155G>T	p.Ala719Ser	missense	Exon 16 of 21	NP_001073271.1	P10253
GAA	NM_001079804.3		c.2155G>T	p.Ala719Ser	missense	Exon 15 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAA	ENST00000302262.8	TSL:1 MANE Select	c.2155G>T	p.Ala719Ser	missense	Exon 15 of 20	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.2155G>T	p.Ala719Ser	missense	Exon 16 of 21	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.2170G>T	p.Ala724Ser	missense	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000256

AC:

AN:

218544

AF XY:

0.000229

show subpopulations

Gnomad AFR exome

AF:

0.000221

Gnomad AMR exome

AF:

0.0000626

Gnomad ASJ exome

AF:

0.00108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000273

Gnomad NFE exome

AF:

0.000342

Gnomad OTH exome

AF:

0.000558

GnomAD4 exome

AF:

0.000179

AC:

259

AN:

1443292

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

124

AN XY:

715934

show subpopulations

African (AFR)

AF:

0.000211

AC:

AN:

33182

American (AMR)

AF:

0.000234

AC:

AN:

42706

Ashkenazi Jewish (ASJ)

AF:

0.000546

AC:

AN:

25638

East Asian (EAS)

AF:

0.00

AC:

AN:

38808

South Asian (SAS)

AF:

0.00

AC:

AN:

83198

European-Finnish (FIN)

AF:

0.000174

AC:

AN:

51688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000186

AC:

205

AN:

1102774

Other (OTH)

AF:

0.000235

AC:

AN:

59562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000191

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41436

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000162

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000290

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Glycogen storage disease, type II (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.0020

(source)

DANN

Benign

0.49

DEOGEN2

Uncertain

0.45

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-0.55

PhyloP100

-1.9

PrimateAI

Benign

0.25

PROVEAN

Benign

0.60

REVEL

Benign

0.21

Sift

Benign

0.41

Sift4G

Benign

0.41

Polyphen

0.0020

Vest4

0.086

MVP

0.60

MPC

0.10

ClinPred

0.0052

GERP RS

-9.3

Varity_R

0.029

gMVP

0.47

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over