rs200007324

Variant names:

• chr17-80109950-T-C
• rs200007324
• NM_000152.5:c.1332T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7 BS1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1332T>C (p.Pro444=) variant in GAA is a synonymous (silent) variant that is not predicted to impact splicing; the nucleotide is not highly conserved (PhyloP 100 way score is -2.4 (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 286018). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 13, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815288/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: -2.81
• Publications: 2 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1332T>C	p.Pro444Pro	synonymous	Exon 9 of 20	NP_000143.2
	GAA	NM_001079803.3		c.1332T>C	p.Pro444Pro	synonymous	Exon 10 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.1332T>C	p.Pro444Pro	synonymous	Exon 9 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1332T>C	p.Pro444Pro	synonymous	Exon 9 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1332T>C	p.Pro444Pro	synonymous	Exon 10 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.1332T>C	p.Pro444Pro	synonymous	Exon 9 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000727 AC: 182 AN: 250288 AF XY: 0.000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00899

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000386 AC: 564 AN: 1460692 Hom.: 2 Cov.: 32 AF XY: 0.000406 AC XY: 295 AN XY: 726666

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000448 AC: 2 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0114 AC: 454 AN: 39692

South Asian (SAS) AF: 0.00103 AC: 89 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111606

Other (OTH) AF: 0.000249 AC: 15 AN: 60356

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152344 Hom.: 0 Cov.: 34 AF XY: 0.000483 AC XY: 36 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00676 AC: 35 AN: 5178

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000434

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Glycogen storage disease, type II (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.64
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs200007324; hg19: chr17-78083749;