rs1042396

Variant names:

• chr17-80110970-G-A
• rs1042396
• NM_000152.5:c.1581G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000152.5(GAA):​c.1581G>A​(p.Arg527Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,613,658 control chromosomes in the GnomAD database, including 56,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.20 (3863 hom., cov: 33)
  • Exomes 𝑓: 0.26 (52328 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.480
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-80110970-G-A is Benign according to our data. Variant chr17-80110970-G-A is described in ClinVar as Benign. ClinVar VariationId is 92466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1581G>A	p.Arg527Arg	synonymous	Exon 11 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1581G>A	p.Arg527Arg	synonymous	Exon 12 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1581G>A	p.Arg527Arg	synonymous	Exon 11 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.1581G>A	p.Arg527Arg	synonymous	Exon 11 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1581G>A	p.Arg527Arg	synonymous	Exon 12 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1596G>A	p.Arg532Arg	synonymous	Exon 11 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30958 AN: 151984 Hom.: 3865 Cov.: 33

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.232 AC: 58151 AN: 251098 AF XY: 0.237

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.263 AC: 384357 AN: 1461556 Hom.: 52328 Cov.: 48 AF XY: 0.262 AC XY: 190598 AN XY: 727070

African (AFR) AF: 0.0608 AC: 2037 AN: 33478

American (AMR) AF: 0.232 AC: 10379 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6644 AN: 26136

East Asian (EAS) AF: 0.120 AC: 4760 AN: 39700

South Asian (SAS) AF: 0.217 AC: 18720 AN: 86256

European-Finnish (FIN) AF: 0.232 AC: 12339 AN: 53208

Middle Eastern (MID) AF: 0.257 AC: 1484 AN: 5768

European-Non Finnish (NFE) AF: 0.281 AC: 312872 AN: 1111912

Other (OTH) AF: 0.250 AC: 15122 AN: 60388

GnomAD4 genome AF: 0.203 AC: 30948 AN: 152102 Hom.: 3863 Cov.: 33 AF XY: 0.202 AC XY: 14983 AN XY: 74340

African (AFR) AF: 0.0632 AC: 2623 AN: 41524

American (AMR) AF: 0.235 AC: 3598 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3468

East Asian (EAS) AF: 0.117 AC: 605 AN: 5166

South Asian (SAS) AF: 0.211 AC: 1016 AN: 4822

European-Finnish (FIN) AF: 0.243 AC: 2570 AN: 10574

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18914 AN: 67942

Other (OTH) AF: 0.221 AC: 466 AN: 2112

Alfa AF: 0.244 Hom.: 3375

Bravo AF: 0.199

Asia WGS AF: 0.152 AC: 528 AN: 3478

EpiCase AF: 0.286

EpiControl AF: 0.286

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.50
PhyloP100		0.48
Mutation Taster		=95/5	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: rs1042396; hg19: chr17-78084769; COSMIC: COSV56407599; COSMIC: COSV56407599;