17-80105870-G-C

Variant names:

• chr17-80105870-G-C
• rs1042395
• NM_000152.5:c.668G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000152.5(GAA):​c.668G>C​(p.Arg223Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• Publications: 61 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 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.

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.668G>C	p.Arg223Pro	missense	Exon 3 of 20	NP_000143.2
	GAA	NM_001079803.3		c.668G>C	p.Arg223Pro	missense	Exon 4 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.668G>C	p.Arg223Pro	missense	Exon 3 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.668G>C	p.Arg223Pro	missense	Exon 3 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.668G>C	p.Arg223Pro	missense	Exon 4 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.668G>C	p.Arg223Pro	missense	Exon 3 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449106 Hom.: 0 Cov.: 58 AF XY: 0.00 AC XY: 0 AN XY: 720346

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108632

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-0.036
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.56
Sift	Benign	0.21	T
Sift4G	Benign	0.13	T
Polyphen		0.80	P
Vest4		0.60
MutPred		0.52		Loss of sheet (P = 0.0817)
MVP		0.99
MPC		0.34
ClinPred		0.98	D
GERP RS		1.8
Varity_R		0.96
gMVP		0.94

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: rs1042395; hg19: chr17-78079669;