chr17-80118272-G-A

Variant names:

• chr17-80118272-G-A
• rs149968110
• NM_000152.5:c.2561G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BP6

The NM_000152.5(GAA):​c.2561G>A​(p.Arg854Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,608,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: -0.434
• Publications: 6 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: Likely_benign. The variant received -2 ACMG points.

• 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 II, glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease due to acid maltase deficiency, late-onset.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0146794915).
• BP6: Variant 17-80118272-G-A is Benign according to our data. Variant chr17-80118272-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286210.

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.2561G>A	p.Arg854Gln	missense	Exon 18 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2561G>A	p.Arg854Gln	missense	Exon 19 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2561G>A	p.Arg854Gln	missense	Exon 18 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.2561G>A	p.Arg854Gln	missense	Exon 18 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2561G>A	p.Arg854Gln	missense	Exon 19 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2576G>A	p.Arg859Gln	missense	Exon 18 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 86 AN: 245916 AF XY: 0.000338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00654

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000197 AC: 287 AN: 1455988 Hom.: 0 Cov.: 35 AF XY: 0.000206 AC XY: 149 AN XY: 723734

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 169 AN: 25698

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39618

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000739 AC: 82 AN: 1108920

Other (OTH) AF: 0.000549 AC: 33 AN: 60134

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.000118 AC: 8 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000559 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000272 AC: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	Glycogen storage disease, type II (4)
-	3	-	not provided (3)
-	1	-	Cardiovascular phenotype (1)
-	-	1	GAA-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.0070
DANN	Benign	0.81
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.43
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.21
Sift	Benign	0.53	T
Sift4G	Benign	0.35	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.71
MPC		0.13
ClinPred		0.010	T
GERP RS		-8.7
Varity_R		0.063
gMVP		0.62
Mutation Taster		=84/16	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: rs149968110; hg19: chr17-78092071;