NM_000152.5:c.921A>T

Variant names:

• chr17-80107862-A-T
• rs1800303
• NM_000152.5:c.921A>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 NM_000152.5: c.921A>T (p.Ala307=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.23520 (569/24196 alleles, with 666 homozygotes) in the African population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92490; 2 star review status) with eight submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel (Specification Version 2.0): BA1.(Classification approved: August 17, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145795/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.11 (1321 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4151 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: -0.320
• Publications: 17 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.921A>T	p.Ala307Ala	synonymous	Exon 5 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.921A>T	p.Ala307Ala	synonymous	Exon 6 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.921A>T	p.Ala307Ala	synonymous	Exon 5 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.921A>T	p.Ala307Ala	synonymous	Exon 5 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.921A>T	p.Ala307Ala	synonymous	Exon 6 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.921A>T	p.Ala307Ala	synonymous	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16531 AN: 152078 Hom.: 1320 Cov.: 33

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0636

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0720 AC: 17622 AN: 244632 AF XY: 0.0713

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0480

Gnomad ASJ exome AF: 0.0727

Gnomad EAS exome AF: 0.000448

Gnomad FIN exome AF: 0.0604

Gnomad NFE exome AF: 0.0652

Gnomad OTH exome AF: 0.0821

GnomAD4 exome AF: 0.0670 AC: 97746 AN: 1459232 Hom.: 4151 Cov.: 57 AF XY: 0.0676 AC XY: 49037 AN XY: 725904

African (AFR) AF: 0.238 AC: 7971 AN: 33444

American (AMR) AF: 0.0516 AC: 2300 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.0713 AC: 1860 AN: 26104

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39654

South Asian (SAS) AF: 0.0865 AC: 7451 AN: 86152

European-Finnish (FIN) AF: 0.0623 AC: 3246 AN: 52084

Middle Eastern (MID) AF: 0.130 AC: 701 AN: 5378

European-Non Finnish (NFE) AF: 0.0627 AC: 69677 AN: 1111610

Other (OTH) AF: 0.0752 AC: 4527 AN: 60226

GnomAD4 genome AF: 0.109 AC: 16541 AN: 152196 Hom.: 1321 Cov.: 33 AF XY: 0.107 AC XY: 7988 AN XY: 74404

African (AFR) AF: 0.230 AC: 9539 AN: 41510

American (AMR) AF: 0.0582 AC: 890 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5170

South Asian (SAS) AF: 0.0741 AC: 357 AN: 4820

European-Finnish (FIN) AF: 0.0636 AC: 675 AN: 10616

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4504 AN: 67990

Other (OTH) AF: 0.104 AC: 221 AN: 2116

Alfa AF: 0.0810 Hom.: 196

Bravo AF: 0.113

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.0689

EpiControl AF: 0.0677

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.67
PhyloP100		-0.32
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800303; hg19: chr17-78081661; COSMIC: COSV56408482; COSMIC: COSV56408482;