rs1042397

Variant names:

• chr17-80118264-G-A
• rs1042397
• NM_000152.5:c.2553G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80118264-G-A
• chr17-80118264-G-C

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.2553G>A (p.Gly851=) in gnomAD v2.1.1 is 0.63818 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.70216) and European Finnish (0.64436) 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: 92481, two star review status), with 6 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/CA145775/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.58 (26128 hom., cov: 32)
  • Exomes 𝑓: 0.61 (275912 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: -0.607
• Publications: 30 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.2553G>A	p.Gly851Gly	synonymous	Exon 18 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2553G>A	p.Gly851Gly	synonymous	Exon 19 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2553G>A	p.Gly851Gly	synonymous	Exon 18 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.2553G>A	p.Gly851Gly	synonymous	Exon 18 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2553G>A	p.Gly851Gly	synonymous	Exon 19 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2568G>A	p.Gly856Gly	synonymous	Exon 18 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88064 AN: 151918 Hom.: 26128 Cov.: 32

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.601

GnomAD2 exomes AF: 0.572 AC: 141807 AN: 248116 AF XY: 0.584

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.277

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.619

GnomAD4 exome AF: 0.611 AC: 890500 AN: 1457544 Hom.: 275912 Cov.: 52 AF XY: 0.612 AC XY: 443382 AN XY: 724652

African (AFR) AF: 0.535 AC: 17885 AN: 33414

American (AMR) AF: 0.441 AC: 19562 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 18172 AN: 25898

East Asian (EAS) AF: 0.278 AC: 11005 AN: 39620

South Asian (SAS) AF: 0.575 AC: 49310 AN: 85798

European-Finnish (FIN) AF: 0.644 AC: 34025 AN: 52852

Middle Eastern (MID) AF: 0.761 AC: 4371 AN: 5740

European-Non Finnish (NFE) AF: 0.630 AC: 699375 AN: 1109702

Other (OTH) AF: 0.612 AC: 36795 AN: 60168

GnomAD4 genome AF: 0.579 AC: 88085 AN: 152036 Hom.: 26128 Cov.: 32 AF XY: 0.576 AC XY: 42822 AN XY: 74302

African (AFR) AF: 0.530 AC: 22012 AN: 41498

American (AMR) AF: 0.493 AC: 7537 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2415 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1417 AN: 5134

South Asian (SAS) AF: 0.557 AC: 2680 AN: 4814

European-Finnish (FIN) AF: 0.656 AC: 6947 AN: 10588

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43173 AN: 67932

Other (OTH) AF: 0.598 AC: 1262 AN: 2112

Alfa AF: 0.603 Hom.: 10147

Bravo AF: 0.567

Asia WGS AF: 0.400 AC: 1396 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	1	3	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	-0.80
CADD	Benign	1.0
DANN	Benign	0.42
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1042397; hg19: chr17-78092063; COSMIC: COSV56406699; COSMIC: COSV56406699;