rs142626724

Variant names:

• chr17-80107716-G-A
• rs142626724
• NM_000152.5:c.852G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107716-G-A
• chr17-80107716-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA198776/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0062 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0084 (72 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: -0.377
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.852G>A	p.Ala284Ala	synonymous	Exon 4 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.852G>A	p.Ala284Ala	synonymous	Exon 5 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.852G>A	p.Ala284Ala	synonymous	Exon 4 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.852G>A	p.Ala284Ala	synonymous	Exon 4 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.852G>A	p.Ala284Ala	synonymous	Exon 5 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.852G>A	p.Ala284Ala	synonymous	Exon 4 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 895 AN: 142998 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00920

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00927

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00204

Gnomad FIN AF: 0.00266

Gnomad MID AF: 0.0199

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00629 AC: 1563 AN: 248578 AF XY: 0.00650

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00775

GnomAD4 exome AF: 0.00840 AC: 12263 AN: 1460388 Hom.: 72 Cov.: 34 AF XY: 0.00830 AC XY: 6033 AN XY: 726540

African (AFR) AF: 0.00176 AC: 59 AN: 33466

American (AMR) AF: 0.00494 AC: 221 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00701 AC: 183 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86246

European-Finnish (FIN) AF: 0.00308 AC: 161 AN: 52312

Middle Eastern (MID) AF: 0.0219 AC: 126 AN: 5766

European-Non Finnish (NFE) AF: 0.00972 AC: 10811 AN: 1111736

Other (OTH) AF: 0.00824 AC: 497 AN: 60346

GnomAD4 genome AF: 0.00624 AC: 893 AN: 143118 Hom.: 2 Cov.: 34 AF XY: 0.00581 AC XY: 404 AN XY: 69592

African (AFR) AF: 0.00161 AC: 63 AN: 39030

American (AMR) AF: 0.00594 AC: 85 AN: 14302

Ashkenazi Jewish (ASJ) AF: 0.00927 AC: 31 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4906

South Asian (SAS) AF: 0.00204 AC: 9 AN: 4408

European-Finnish (FIN) AF: 0.00266 AC: 25 AN: 9406

Middle Eastern (MID) AF: 0.0179 AC: 5 AN: 280

European-Non Finnish (NFE) AF: 0.0100 AC: 647 AN: 64660

Other (OTH) AF: 0.0105 AC: 20 AN: 1912

Alfa AF: 0.00767 Hom.: 1

Bravo AF: 0.00629

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type II (5)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		-0.38
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs142626724; hg19: chr17-78081515;