rs1800304

Variant names:

• chr17-80108705-G-A
• rs1800304
• NM_000152.5:c.1203G>A

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.1203G>A (p.Gln401=) in gnomAD v2.1.1 is 0.74003 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77901) and European Finnish (0.76403) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92461, two star review status), with 7 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/CA145749/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.65 (33470 hom., cov: 32)
  • Exomes 𝑓: 0.71 (372540 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: 3.60
• Publications: 39 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.1203G>A	p.Gln401Gln	synonymous	Exon 8 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1203G>A	p.Gln401Gln	synonymous	Exon 9 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1203G>A	p.Gln401Gln	synonymous	Exon 8 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.1203G>A	p.Gln401Gln	synonymous	Exon 8 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1203G>A	p.Gln401Gln	synonymous	Exon 9 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1203G>A	p.Gln401Gln	synonymous	Exon 8 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99563 AN: 151984 Hom.: 33457 Cov.: 32

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.669 AC: 165746 AN: 247614 AF XY: 0.684

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.764

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.722

GnomAD4 exome AF: 0.712 AC: 1039092 AN: 1460166 Hom.: 372540 Cov.: 81 AF XY: 0.713 AC XY: 517684 AN XY: 726364

African (AFR) AF: 0.532 AC: 17823 AN: 33478

American (AMR) AF: 0.489 AC: 21804 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20439 AN: 26132

East Asian (EAS) AF: 0.560 AC: 22202 AN: 39676

South Asian (SAS) AF: 0.673 AC: 58064 AN: 86216

European-Finnish (FIN) AF: 0.766 AC: 39901 AN: 52114

Middle Eastern (MID) AF: 0.795 AC: 4585 AN: 5764

European-Non Finnish (NFE) AF: 0.730 AC: 811470 AN: 1111822

Other (OTH) AF: 0.709 AC: 42804 AN: 60338

GnomAD4 genome AF: 0.655 AC: 99607 AN: 152102 Hom.: 33470 Cov.: 32 AF XY: 0.653 AC XY: 48547 AN XY: 74376

African (AFR) AF: 0.530 AC: 21990 AN: 41496

American (AMR) AF: 0.556 AC: 8509 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2674 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2767 AN: 5146

South Asian (SAS) AF: 0.661 AC: 3193 AN: 4832

European-Finnish (FIN) AF: 0.775 AC: 8214 AN: 10598

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50014 AN: 67958

Other (OTH) AF: 0.667 AC: 1405 AN: 2106

Alfa AF: 0.700 Hom.: 29218

Bravo AF: 0.635

Asia WGS AF: 0.587 AC: 2044 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.741

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	Glycogen storage disease, type II (7)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.9
DANN	Benign	0.47
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800304; hg19: chr17-78082504; COSMIC: COSV56407152; COSMIC: COSV56407152;