rs1042396

Positions:

• chr17-80110970-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000152.5(GAA):​c.1581G>A​(p.Arg527Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,613,658 control chromosomes in the GnomAD database, including 56,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3863 hom., cov: 33)
  • Exomes 𝑓: 0.26 (52328 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.480

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-80110970-G-A is Benign according to our data. Variant chr17-80110970-G-A is described in ClinVar as [Benign]. Clinvar id is 92466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80110970-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1581G>A	p.Arg527Arg	synonymous_variant	11/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1581G>A	p.Arg527Arg	synonymous_variant	11/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30958 AN: 151984 Hom.: 3865 Cov.: 33

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.232 AC: 58151 AN: 251098 Hom.: 7342 AF XY: 0.237 AC XY: 32181 AN XY: 135800

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.263 AC: 384357 AN: 1461556 Hom.: 52328 Cov.: 48 AF XY: 0.262 AC XY: 190598 AN XY: 727070

Gnomad4 AFR exome AF: 0.0608

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.203 AC: 30948 AN: 152102 Hom.: 3863 Cov.: 33 AF XY: 0.202 AC XY: 14983 AN XY: 74340

Gnomad4 AFR AF: 0.0632

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.221

Alfa AF: 0.250 Hom.: 2622

Bravo AF: 0.199

Asia WGS AF: 0.152 AC: 528 AN: 3478

EpiCase AF: 0.286

EpiControl AF: 0.286

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 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
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.50

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: rs1042396; hg19: chr17-78084769; COSMIC: COSV56407599; COSMIC: COSV56407599;