dbSNP rs12452721: GAA:c.547-39T>G (chr17-80105710-T-G) – 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.547-39T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,603,762 control chromosomes in the GnomAD database, including 405,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33614 hom., cov: 31)

Exomes 𝑓: 0.71 ( 371596 hom. )

Consequence

GAA
NM_000152.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.535

Publications

15 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=-0.9).

BP6

Variant 17-80105710-T-G is Benign according to our data. Variant chr17-80105710-T-G is described in ClinVar as Benign. ClinVar VariationId is 255363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 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.547-39T>G	intron	N/A	NP_000143.2	P10253
GAA	NM_001079803.3		c.547-39T>G	intron	N/A	NP_001073271.1	P10253
GAA	NM_001079804.3		c.547-39T>G	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.547-39T>G	intron	N/A	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.547-39T>G	intron	N/A	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.547-39T>G	intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99838

AN:

151858

Hom.:

33601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.537

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.770

Gnomad EAS

AF:

0.539

Gnomad SAS

AF:

0.665

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.669

GnomAD2 exomes

AF:

0.668

AC:

164713

AN:

246584

AF XY:

0.683

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.474

Gnomad ASJ exome

AF:

0.779

Gnomad EAS exome

AF:

0.528

Gnomad FIN exome

AF:

0.752

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.712

AC:

1034169

AN:

1451786

Hom.:

371596

Cov.:

AF XY:

0.713

AC XY:

515518

AN XY:

722568

show subpopulations

African (AFR)

AF:

0.540

AC:

17996

AN:

33332

American (AMR)

AF:

0.489

AC:

21842

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

20416

AN:

26098

East Asian (EAS)

AF:

0.560

AC:

22188

AN:

39652

South Asian (SAS)

AF:

0.677

AC:

58264

AN:

86118

European-Finnish (FIN)

AF:

0.761

AC:

37501

AN:

49294

Middle Eastern (MID)

AF:

0.797

AC:

4536

AN:

5690

European-Non Finnish (NFE)

AF:

0.731

AC:

808685

AN:

1106794

Other (OTH)

AF:

0.711

AC:

42741

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

15408

30816

46224

61632

77040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19784

39568

59352

79136

98920

<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:

0.657

AC:

99881

AN:

151976

Hom.:

33614

Cov.:

AF XY:

0.655

AC XY:

48634

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.537

AC:

22246

AN:

41416

American (AMR)

AF:

0.558

AC:

8524

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

2672

AN:

3468

East Asian (EAS)

AF:

0.539

AC:

2783

AN:

5160

South Asian (SAS)

AF:

0.664

AC:

3201

AN:

4822

European-Finnish (FIN)

AF:

0.775

AC:

8188

AN:

10564

Middle Eastern (MID)

AF:

0.847

AC:

249

AN:

294

European-Non Finnish (NFE)

AF:

0.736

AC:

50016

AN:

67958

Other (OTH)

AF:

0.668

AC:

1409

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1743

3486

5230

6973

8716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.707

Hom.:

7247

Bravo

AF:

0.638

Asia WGS

AF:

0.588

AC:

2049

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Glycogen storage disease, type II (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

(source)

DANN

Benign

0.65

PhyloP100

-0.54

Mutation Taster

=100/0

polymorphism (auto)

(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