rs1042393

chr17-80105798-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. 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. 15/20 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:14
• Conservation: PhyloP100: -0.0300

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• 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 id is 92486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80105798-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.596A>G	p.His199Arg	missense_variant	3/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.596A>G	p.His199Arg	missense_variant	3/20	1	NM_000152.5	P1

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

GnomAD3 exomes AF: 0.667 AC: 166175 AN: 248970 Hom.: 57111 AF XY: 0.682 AC XY: 91983 AN XY: 134958

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 SAS exome AF: 0.661

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

Gnomad4 AFR exome AF: 0.539

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 0.559

Gnomad4 SAS exome AF: 0.662

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.709

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

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.647

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.669

Alfa AF: 0.716 Hom.: 45443

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

Significance: Benign

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -

not provided Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.976% in gnomAD_ExomesFounderPop) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.8 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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;.;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.021	T;T;.;T
MetaRNN	Benign	9.0e-7	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;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

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

Publications

LitVar

Other links and lift over

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