NM_000152.5:c.1285C>G

Variant names:

• chr17-80108787-C-G
• rs528369909
• NM_000152.5:c.1285C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000152.5(GAA):​c.1285C>G​(p.Gln429Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,607,578 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q429R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (11 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.371
• Publications: 5 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 -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000152.5
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008360773).
• BP6: Variant 17-80108787-C-G is Benign according to our data. Variant chr17-80108787-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 291064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1285C>G	p.Gln429Glu	missense	Exon 8 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1285C>G	p.Gln429Glu	missense	Exon 9 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1285C>G	p.Gln429Glu	missense	Exon 8 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.1285C>G	p.Gln429Glu	missense	Exon 8 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1285C>G	p.Gln429Glu	missense	Exon 9 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1285C>G	p.Gln429Glu	missense	Exon 8 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00103 AC: 241 AN: 233994 AF XY: 0.00125

Gnomad AFR exome AF: 0.000487

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000476 AC: 692 AN: 1455262 Hom.: 11 Cov.: 36 AF XY: 0.000651 AC XY: 471 AN XY: 723576

African (AFR) AF: 0.000479 AC: 16 AN: 33372

American (AMR) AF: 0.0000454 AC: 2 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39428

South Asian (SAS) AF: 0.00707 AC: 604 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109490

Other (OTH) AF: 0.00102 AC: 61 AN: 60094

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74464

African (AFR) AF: 0.000529 AC: 22 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00662 AC: 32 AN: 4832

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: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.00117 AC: 141

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GAA-related disorder (1)
-	-	1	Glycogen storage disease, type II (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	6.7
DANN	Benign	0.33
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.37
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.20	N
REVEL	Uncertain	0.33
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.90
MPC		0.12
ClinPred		0.0023	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.51
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs528369909; hg19: chr17-78082586;