chr17-80104717-G-T

Variant names:

• chr17-80104717-G-T
• rs550609502
• NM_000152.5:c.131G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.131G>T variant in GAA is predicted to result in the substitution of glycine by valine at amino acid 44 (p.Gly44Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (32/126504 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.245 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 325774). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM2_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814793/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8 B:1
• Conservation: PhyloP100: -0.0340
• Publications: 15 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.131G>T	p.Gly44Val	missense	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.131G>T	p.Gly44Val	missense	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.131G>T	p.Gly44Val	missense	Exon 2 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.131G>T	p.Gly44Val	missense	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.131G>T	p.Gly44Val	missense	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.131G>T	p.Gly44Val	missense	Exon 2 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000122 AC: 30 AN: 246842 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1460276 Hom.: 0 Cov.: 31 AF XY: 0.000209 AC XY: 152 AN XY: 726412

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000256 AC: 285 AN: 1111772

Other (OTH) AF: 0.000215 AC: 13 AN: 60336

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74296

African (AFR) AF: 0.0000966 AC: 4 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000825 AC: 10

EpiCase AF: 0.000218

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	1	Glycogen storage disease, type II (5)
-	4	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.9
DANN	Benign	0.67
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.034
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.24
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.17
MutPred		0.34		Loss of glycosylation at S43 (P = 0.036)
MVP		0.82
MPC		0.19
ClinPred		0.020	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.49
Mutation Taster		=75/25	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: rs550609502; hg19: chr17-78078516; COSMIC: COSV106099507; COSMIC: COSV106099507;