rs2289536

Positions:

• chr17-80105033-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000152.5(GAA):​c.447G>A​(p.Thr149=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,612,848 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (40 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.40

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=-0.56).
• BP6: Variant 17-80105033-G-A is Benign according to our data. Variant chr17-80105033-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80105033-G-A is described in Lovd as [Likely_benign]. Variant chr17-80105033-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00395 (602/152246) while in subpopulation EAS AF= 0.0334 (173/5172). AF 95% confidence interval is 0.0294. There are 7 homozygotes in gnomad4. There are 286 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.447G>A	p.Thr149=	synonymous_variant	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.447G>A	p.Thr149=	synonymous_variant	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 601 AN: 152128 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00509 AC: 1257 AN: 246846 Hom.: 11 AF XY: 0.00501 AC XY: 674 AN XY: 134562

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.0294

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00542 AC: 7923 AN: 1460602 Hom.: 40 Cov.: 36 AF XY: 0.00545 AC XY: 3957 AN XY: 726620

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.0292

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.000977

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00395 AC: 602 AN: 152246 Hom.: 7 Cov.: 33 AF XY: 0.00384 AC XY: 286 AN XY: 74434

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00470

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00414 Hom.: 1

Bravo AF: 0.00414

Asia WGS AF: 0.0200 AC: 73 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2018	Variant summary: The GAA c.447G>A (p.Thr149Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change that is not located in any known domain (InterPro). One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1372/272790 control chromosomes (12 homozygotes) at a frequency of 0.0050295, which is approximately equal to the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
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	Genetic Services Laboratory, University of Chicago	Apr 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Glycogen storage disease, type II Benign:6

Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.447G>A (p.Thr149=) variant in GAA has been reported in one individual with Glycogen Storage Disease Type II (PMID: 18458862). This variant has been reported as a benign variant (by UChicago Genetics Services Laboratory, GeneDx, Invitae, EGL, and PreventionGenetics) and a VUS (by Illumina) in ClinVar (Variation ID: 129121). This variant has been identified in 2.97% (590/19862) of East Asian chromosomes and 13 homozygotes as well as other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2289536). 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 its frequency in the general population. ACMG/AMP Criteria applied: BA1, BP7, BP4 (Richards 2015). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2020

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	-0.56
CADD	Benign	1.7
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2289536; hg19: chr17-78078832; COSMIC: COSV100162957; COSMIC: COSV100162957;