rs143347747

Variant names:

• chr17-80117663-C-T
• rs143347747
• NM_000152.5:c.2395C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2_Supporting PM3_Supporting PP4_Moderate BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2395C>T variant in GAA is a missense variant predicted to cause substitution of His by Tyr at amino acid 799 (p.His799Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00038 (6/15954 alleles) in the African population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.443 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It only has been reported in one case as LOPD, in which has unknown phase concurrence in compound heterozygous with c.-32-13T>G (PMID:22958975). Thus met PM3_supporting. The LOPD case has been reported to have GAA residue level 0.25 (normal cutoff unknown. But average of 20 LOPD patients is 8.35, so <10% of normal mean control level). Thus PP4_moderate is applied. There is a ClinVar entry for this variant (Variation ID: 284886, 2 star review status) with 8 submitters classifying the variant as Uncertain significance with no conflicts. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_moderate, PM3_supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP, September 5, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815726/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:11
• Conservation: PhyloP100: 1.22
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.2395C>T	p.His799Tyr	missense	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2395C>T	p.His799Tyr	missense	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2395C>T	p.His799Tyr	missense	Exon 17 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.2395C>T	p.His799Tyr	missense	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2395C>T	p.His799Tyr	missense	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2410C>T	p.His804Tyr	missense	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248542 AF XY: 0.0000222

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460582 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 726604

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44716

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.0000331 AC: 2 AN: 60372

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74474

African (AFR) AF: 0.000313 AC: 13 AN: 41570

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	7	-	Glycogen storage disease, type II (7)
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.13	N
PhyloP100		1.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.44
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.69
MVP		0.75
MPC		0.13
ClinPred		0.021	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.74
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs143347747; hg19: chr17-78091462;