dbSNP rs2289536: GAA:p.Thr149Thr (chr17-80105033-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000152.5(GAA):c.447G>A(p.Thr149Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,612,848 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 40 hom. )

Consequence

GAA
NM_000152.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.40

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 17-80105033-G-A is Benign according to our data. Variant chr17-80105033-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.39 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00395 (602/152246) while in subpopulation EAS AF = 0.0334 (173/5172). AF 95% confidence interval is 0.0294. There are 7 homozygotes in GnomAd4. There are 286 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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.447G>A	p.Thr149Thr	synonymous	Exon 2 of 20	NP_000143.2	P10253
GAA	NM_001079803.3		c.447G>A	p.Thr149Thr	synonymous	Exon 3 of 21	NP_001073271.1	P10253
GAA	NM_001079804.3		c.447G>A	p.Thr149Thr	synonymous	Exon 2 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.447G>A	p.Thr149Thr	synonymous	Exon 2 of 20	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.447G>A	p.Thr149Thr	synonymous	Exon 3 of 21	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.447G>A	p.Thr149Thr	synonymous	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0332

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00509

AC:

1257

AN:

246846

AF XY:

0.00501

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00460

Gnomad OTH exome

AF:

0.00461

GnomAD4 exome

AF:

0.00542

AC:

7923

AN:

1460602

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3957

AN XY:

726620

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26132

East Asian (EAS)

AF:

0.0292

AC:

1158

AN:

39698

South Asian (SAS)

AF:

0.00292

AC:

252

AN:

86256

European-Finnish (FIN)

AF:

0.000977

AC:

AN:

52178

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00535

AC:

5946

AN:

1111994

Other (OTH)

AF:

0.00614

AC:

371

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

505

1010

1515

2020

2525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.00395

AC:

602

AN:

152246

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41540

American (AMR)

AF:

0.00144

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.0334

AC:

173

AN:

5172

South Asian (SAS)

AF:

0.00394

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00470

AC:

320

AN:

68014

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00424

Hom.:

Bravo

AF:

0.00414

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00373

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (6)

not specified (6)

not provided (3)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.7

(source)

DANN

Benign

0.80

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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