rs1042397

Positions:

• chr17-80118264-G-A
• chr17-80118264-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.2553G>A (p.Gly851=) in gnomAD v2.1.1 is 0.63818 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.70216) and European Finnish (0.64436) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92481, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145775/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.58 (26128 hom., cov: 32)
  • Exomes 𝑓: 0.61 (275912 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:13
• Conservation: PhyloP100: -0.607

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 -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2553G>A	p.Gly851=	synonymous_variant	18/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2553G>A	p.Gly851=	synonymous_variant	18/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88064 AN: 151918 Hom.: 26128 Cov.: 32

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.601

GnomAD3 exomes AF: 0.572 AC: 141807 AN: 248116 Hom.: 42414 AF XY: 0.584 AC XY: 78379 AN XY: 134258

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.277

Gnomad SAS exome AF: 0.573

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.619

GnomAD4 exome AF: 0.611 AC: 890500 AN: 1457544 Hom.: 275912 Cov.: 52 AF XY: 0.612 AC XY: 443382 AN XY: 724652

Gnomad4 AFR exome AF: 0.535

Gnomad4 AMR exome AF: 0.441

Gnomad4 ASJ exome AF: 0.702

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.644

Gnomad4 NFE exome AF: 0.630

Gnomad4 OTH exome AF: 0.612

GnomAD4 genome AF: 0.579 AC: 88085 AN: 152036 Hom.: 26128 Cov.: 32 AF XY: 0.576 AC XY: 42822 AN XY: 74302

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.493

Gnomad4 ASJ AF: 0.696

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.557

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.598

Alfa AF: 0.603 Hom.: 10147

Bravo AF: 0.567

Asia WGS AF: 0.400 AC: 1396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 23, 2020	The highest continental population minor allele frequency for c.2553G>A (p.Gly851=) in gnomAD v2.1.1 is 0.63818 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.70216) and European Finnish (0.64436) populations. These allele frequencies are higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92481, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -

not specified Benign:4

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23418865) -
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: 70.344% 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.6 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2015

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	-0.80
CADD	Benign	1.0
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1042397; hg19: chr17-78092063; COSMIC: COSV56406699; COSMIC: COSV56406699;