rs1042393

Variant names:

• chr17-80105798-A-G
• rs1042393
• NM_000152.5:c.596A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80105798-A-G
• chr17-80105798-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.596A>G​(p.His199Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,610,784 control chromosomes in the GnomAD database, including 405,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H199C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.66 (33560 hom., cov: 32)
  • Exomes 𝑓: 0.71 (371799 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: -0.0300
• Publications: 68 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 -19 ACMG points.

• 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=8.970628E-7).
• BP6: Variant 17-80105798-A-G is Benign according to our data. Variant chr17-80105798-A-G is described in ClinVar as Benign. ClinVar VariationId is 92486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 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.596A>G	p.His199Arg	missense	Exon 3 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.596A>G	p.His199Arg	missense	Exon 4 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.596A>G	p.His199Arg	missense	Exon 3 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.596A>G	p.His199Arg	missense	Exon 3 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.596A>G	p.His199Arg	missense	Exon 4 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.596A>G	p.His199Arg	missense	Exon 3 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99760 AN: 151922 Hom.: 33547 Cov.: 32

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.669

GnomAD2 exomes AF: 0.667 AC: 166175 AN: 248970 AF XY: 0.682

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.529

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.711 AC: 1037403 AN: 1458744 Hom.: 371799 Cov.: 55 AF XY: 0.712 AC XY: 516674 AN XY: 725778

African (AFR) AF: 0.539 AC: 18045 AN: 33470

American (AMR) AF: 0.489 AC: 21882 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20443 AN: 26136

East Asian (EAS) AF: 0.559 AC: 22201 AN: 39690

South Asian (SAS) AF: 0.662 AC: 57071 AN: 86248

European-Finnish (FIN) AF: 0.763 AC: 38833 AN: 50862

Middle Eastern (MID) AF: 0.797 AC: 4588 AN: 5756

European-Non Finnish (NFE) AF: 0.730 AC: 811548 AN: 1111514

Other (OTH) AF: 0.709 AC: 42792 AN: 60358

GnomAD4 genome AF: 0.656 AC: 99802 AN: 152040 Hom.: 33560 Cov.: 32 AF XY: 0.654 AC XY: 48586 AN XY: 74312

African (AFR) AF: 0.536 AC: 22214 AN: 41450

American (AMR) AF: 0.558 AC: 8525 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2670 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2790 AN: 5162

South Asian (SAS) AF: 0.647 AC: 3120 AN: 4822

European-Finnish (FIN) AF: 0.775 AC: 8201 AN: 10582

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50030 AN: 67964

Other (OTH) AF: 0.669 AC: 1411 AN: 2110

Alfa AF: 0.702 Hom.: 70119

Bravo AF: 0.638

TwinsUK AF: 0.722 AC: 2678

ALSPAC AF: 0.724 AC: 2791

ESP6500AA AF: 0.544 AC: 2398

ESP6500EA AF: 0.738 AC: 6349

ExAC AF: 0.674 AC: 81812

Asia WGS AF: 0.577 AC: 2009 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.742

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.17
DANN	Benign	0.42
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.021	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-3.4	N
PhyloP100		-0.030
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.18
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.13
ClinPred		0.012	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs1042393; hg19: chr17-78079597; COSMIC: COSV56406840; COSMIC: COSV56406840;