Variant 17-80105710-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000302262.8(GAA):c.547-39T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,603,762 control chromosomes in the GnomAD database, including 405,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33614 hom., cov: 31)

Exomes 𝑓: 0.71 ( 371596 hom. )

Consequence

GAA
ENST00000302262.8 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.535

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-80105710-T-G is Benign according to our data. Variant chr17-80105710-T-G is described in ClinVar as [Benign]. Clinvar id is 255363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80105710-T-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	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.547-39T>G		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.547-39T>G		intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99838

AN:

151858

Hom.:

33601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.537

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.770

Gnomad EAS

AF:

0.539

Gnomad SAS

AF:

0.665

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.669

GnomAD3 exomes

AF:

0.668

AC:

164713

AN:

246584

Hom.:

56633

AF XY:

0.683

AC XY:

91427

AN XY:

133854

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.474

Gnomad ASJ exome

AF:

0.779

Gnomad EAS exome

AF:

0.528

Gnomad SAS exome

AF:

0.677

Gnomad FIN exome

AF:

0.752

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.712

AC:

1034169

AN:

1451786

Hom.:

371596

Cov.:

AF XY:

0.713

AC XY:

515518

AN XY:

722568

show subpopulations

Gnomad4 AFR exome

AF:

0.540

Gnomad4 AMR exome

AF:

0.489

Gnomad4 ASJ exome

AF:

0.782

Gnomad4 EAS exome

AF:

0.560

Gnomad4 SAS exome

AF:

0.677

Gnomad4 FIN exome

AF:

0.761

Gnomad4 NFE exome

AF:

0.731

Gnomad4 OTH exome

AF:

0.711

GnomAD4 genome

AF:

0.657

AC:

99881

AN:

151976

Hom.:

33614

Cov.:

AF XY:

0.655

AC XY:

48634

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.537

Gnomad4 AMR

AF:

0.558

Gnomad4 ASJ

AF:

0.770

Gnomad4 EAS

AF:

0.539

Gnomad4 SAS

AF:

0.664

Gnomad4 FIN

AF:

0.775

Gnomad4 NFE

AF:

0.736

Gnomad4 OTH

AF:

0.668

Alfa

AF:

0.712

Hom.:

7143

Bravo

AF:

0.638

Asia WGS

AF:

0.588

AC:

2049

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
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)	Aug 07, 2017	- -

Glycogen storage disease, type II

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.547-39T>G variant in GAA has been reported in at least 6 individuals with suspected glycogen storage disease II (PMID: 28032299, 25681614), and has also been reported in ClinVar (VariationID: 255363) as benign by EGL Genetic Diagnostics and PreventionGenetics. This variant has been identified in 77.9% (8028/10312) of Ashkenazi Jewish chromosomes, including 3120 homozygotes, and is present at high frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12452721). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for glycogen storage disease II in an autosomal recessive manner based on high frequency in the general population. ACMG/AMP Criteria applied: BA1, BP7, BP4 (Richards 2015). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	This variant is associated with the following publications: (PMID: 30595407, 24008937, 25681614, 28032299) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

DANN

Benign

0.65

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

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