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
ENST00000302262.8 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004151

Clinical Significance

Benign reviewed by expert panel U:1B:15

Conservation

PhyloP100: -0.139

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.547-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.547-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99789

AN:

151900

Hom.:

33566

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.713

AC XY:

517028

AN XY:

725362

show subpopulations

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.:

AF XY:

0.654

AC XY:

48619

AN XY:

74298

show subpopulations

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:1Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

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. -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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: 77.996% 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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over