17-80105745-C-G

Position:

• chr17-80105745-C-G

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.547-4C>G in gnomAD v2.1.1 is 0.7403 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77927) and European Finnish (0.75914) 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: 92485, 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/CA145784/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.66 (33579 hom., cov: 32)
  • Exomes 𝑓: 0.71 (372392 hom.)
• Consequence: GAA NM_000152.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004151
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: -0.139

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.547-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.547-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99789 AN: 151900 Hom.: 33566 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: 0.658

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.667

GnomAD3 exomes AF: 0.669 AC: 166767 AN: 249394 Hom.: 57428 AF XY: 0.683 AC XY: 92305 AN XY: 135114

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: 0.669

Gnomad FIN exome AF: 0.759

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.712 AC: 1037625 AN: 1457634 Hom.: 372392 Cov.: 50 AF XY: 0.713 AC XY: 517028 AN XY: 725362

Gnomad4 AFR exome AF: 0.539

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.670

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.710

GnomAD4 genome AF: 0.657 AC: 99831 AN: 152018 Hom.: 33579 Cov.: 32 AF XY: 0.654 AC XY: 48619 AN XY: 74298

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.667

Alfa AF: 0.707 Hom.: 9153

Bravo AF: 0.638

Asia WGS AF: 0.580 AC: 2020 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.741

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Benign:6

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.547-4C>G in gnomAD v2.1.1 is 0.7403 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77927) and European Finnish (0.75914) 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: 92485, 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, criteria provided, single submitter	clinical testing	Invitae	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	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	PreventionGenetics, part of Exact Sciences	-	- -
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	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+	-	- -

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	- -
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: 77.996% 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. -

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	-0.85
CADD	Benign	4.6
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0
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: rs3816256; hg19: chr17-78079544; COSMIC: COSV56408701; COSMIC: COSV56408701;