rs1800307

Variant names:

• chr17-80112072-G-A
• rs1800307
• NM_000152.5:c.1726G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80112072-G-A
• chr17-80112072-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 6P and 16B. PM1 PM5 PP2 PP3 BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.1726G>A​(p.Gly576Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,613,972 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G576D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0091 (83 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (723 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:11 O:3
• Conservation: PhyloP100: 9.30
• Publications: 102 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000152.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80112073-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526516.
• 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP6: Variant 17-80112072-G-A is Benign according to our data. Variant chr17-80112072-G-A is described in ClinVar as Benign|other. ClinVar VariationId is 92467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

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.1726G>A	p.Gly576Ser	missense	Exon 12 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1726G>A	p.Gly576Ser	missense	Exon 13 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1726G>A	p.Gly576Ser	missense	Exon 12 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.1726G>A	p.Gly576Ser	missense	Exon 12 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1726G>A	p.Gly576Ser	missense	Exon 13 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1741G>A	p.Gly581Ser	missense	Exon 12 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1380 AN: 152194 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0177 AC: 4439 AN: 251298 AF XY: 0.0175

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00905

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00826 AC: 12080 AN: 1461660 Hom.: 723 Cov.: 31 AF XY: 0.00885 AC XY: 6438 AN XY: 727166

African (AFR) AF: 0.000388 AC: 13 AN: 33476

American (AMR) AF: 0.00928 AC: 415 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26126

East Asian (EAS) AF: 0.170 AC: 6749 AN: 39692

South Asian (SAS) AF: 0.0273 AC: 2352 AN: 86258

European-Finnish (FIN) AF: 0.0133 AC: 709 AN: 53312

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000943 AC: 1048 AN: 1111926

Other (OTH) AF: 0.0127 AC: 766 AN: 60382

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152312 Hom.: 83 Cov.: 33 AF XY: 0.0105 AC XY: 783 AN XY: 74470

African (AFR) AF: 0.000962 AC: 40 AN: 41576

American (AMR) AF: 0.0106 AC: 163 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.147 AC: 760 AN: 5174

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4824

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68012

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00698 Hom.: 275

Bravo AF: 0.00842

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0179 AC: 2170

Asia WGS AF: 0.0810 AC: 283 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Glycogen storage disease, type II (6)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.34
MPC		0.54
ClinPred		0.078	T
GERP RS		4.7
Varity_R		0.94
gMVP		0.93
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800307; hg19: chr17-78085871; COSMIC: COSV56407575; COSMIC: COSV56407575;