Genetic Variant GAA:c.858+30T>C (chr17-80107752-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000152.5(GAA):c.858+30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,609,190 control chromosomes in the GnomAD database, including 404,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 33310 hom., cov: 33)

Exomes 𝑓: 0.71 ( 371270 hom. )

Consequence

GAA
NM_000152.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.40

Publications

11 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 17-80107752-T-C is Benign according to our data. Variant chr17-80107752-T-C is described in ClinVar as Benign. ClinVar VariationId is 167111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
GAA	NM_000152.5	MANE Select	c.858+30T>C	intron	N/A	NP_000143.2	P10253
GAA	NM_001079803.3		c.858+30T>C	intron	N/A	NP_001073271.1	P10253
GAA	NM_001079804.3		c.858+30T>C	intron	N/A	NP_001073272.1	P10253

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GAA	ENST00000302262.8	TSL:1 MANE Select	c.858+30T>C	intron	N/A	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.858+30T>C	intron	N/A	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.858+30T>C	intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.655

AC:

99265

AN:

151664

Hom.:

33298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.557

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.538

Gnomad SAS

AF:

0.655

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.836

Gnomad NFE

AF:

0.735

Gnomad OTH

AF:

0.666

GnomAD2 exomes

AF:

0.662

AC:

158806

AN:

239982

AF XY:

0.676

show subpopulations

Gnomad AFR exome

AF:

0.523

Gnomad AMR exome

AF:

0.470

Gnomad ASJ exome

AF:

0.779

Gnomad EAS exome

AF:

0.522

Gnomad FIN exome

AF:

0.759

Gnomad NFE exome

AF:

0.732

Gnomad OTH exome

AF:

0.719

GnomAD4 exome

AF:

0.711

AC:

1036358

AN:

1457410

Hom.:

371270

Cov.:

AF XY:

0.712

AC XY:

516033

AN XY:

724850

show subpopulations

African (AFR)

AF:

0.533

AC:

17791

AN:

33394

American (AMR)

AF:

0.488

AC:

21668

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

20377

AN:

26058

East Asian (EAS)

AF:

0.560

AC:

22161

AN:

39578

South Asian (SAS)

AF:

0.667

AC:

57399

AN:

86116

European-Finnish (FIN)

AF:

0.765

AC:

39657

AN:

51832

Middle Eastern (MID)

AF:

0.795

AC:

4566

AN:

5740

European-Non Finnish (NFE)

AF:

0.730

AC:

810138

AN:

1110180

Other (OTH)

AF:

0.708

AC:

42601

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

17875

35750

53625

71500

89375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19898

39796

59694

79592

99490

<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:

0.654

AC:

99307

AN:

151780

Hom.:

33310

Cov.:

AF XY:

0.652

AC XY:

48372

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.530

AC:

21966

AN:

41408

American (AMR)

AF:

0.556

AC:

8488

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2660

AN:

3458

East Asian (EAS)

AF:

0.538

AC:

2765

AN:

5140

South Asian (SAS)

AF:

0.654

AC:

3148

AN:

4816

European-Finnish (FIN)

AF:

0.775

AC:

8204

AN:

10586

Middle Eastern (MID)

AF:

0.844

AC:

238

AN:

282

European-Non Finnish (NFE)

AF:

0.735

AC:

49849

AN:

67798

Other (OTH)

AF:

0.666

AC:

1403

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1726

3452

5177

6903

8629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.704

Hom.:

7101

Bravo

AF:

0.635

Asia WGS

AF:

0.582

AC:

2025

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Glycogen storage disease, type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.099

(source)

DANN

Benign

0.21

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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