rs148578399

chr17-80107590-G-Achr17-80107590-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BP6_Strong

The NM_000152.5(GAA):c.726G>A(p.Ala242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. A242A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:5 B:7
• Conservation: PhyloP100: -4.12

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 17-80107590-G-A is Benign according to our data. Variant chr17-80107590-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 285366.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5, Benign=1}. Variant chr17-80107590-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.726G>A	p.Ala242=	synonymous_variant	4/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.726G>A	p.Ala242=	synonymous_variant	4/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152090 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251126 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135854

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1460916 Hom.: 0 Cov.: 33 AF XY: 0.0000853 AC XY: 62 AN XY: 726784

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152208 Hom.: 0 Cov.: 34 AF XY: 0.000820 AC XY: 61 AN XY: 74404

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000724 Hom.: 0

Bravo AF: 0.00100

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 19, 2023	The NM_000152.5:c.726G>A variant in GAA is a synonymous (silent) variant (p.Ala242=) that is predicted to impact splicing. This variant has been detected in at least 10 individuals with low GAA activity. Of those individuals, 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.726G>A/c.525delT; 5 patients with the genotype c.−32-13T>G; 726G>A, confirmed in trans in 3 patients, PMID: 36310651; c.726G>A / c.671G>A; c.726G>A / c.1979G>A; c.726G>A and c.2560C>T), however there is no diagnosis of Pompe disease and PM3 and PP4 are not met. The computational splicing predictor SpliceAI gives a score of 0.96 for acceptor gain, predicting that the variant creates a new cryptic splice site that is stronger than the original splice site. VarSeak also classifies this variant as having a likely splicing effect by generating a cryptic splice site 35 nucleotides downstream of the authentic splice site with a higher score, meeting PP3. This is confirmed by RNA sequencing data for an individual with the c.726G>A variant demonstrated that the variant impacts splicing by introducing an alternate splice site that results in exon shrinkage. The data suggest that this results in a frameshift and introduces a premature termination codon, however the expression is not reduced, indicating a truncated protein is produced (PMID: 35304488), meeting PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 285366, 1 star review status) with 10 submitters classifying the variant as VUS (4 submitters), likely benign (3 submitters), and benign (1 submitter). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PP3, PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Sept. 19, 2023) -
Likely benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.726G>A (p.Ala242=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL and Illumina), a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories), and a benign variant (by Invitae) in ClinVar (Variation ID: 285366). This variant has been identified in 0.2769% (69/24916) of African chromosomes, including 1 homozygote, and 0.04516% (16/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148578399). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015). -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 17, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.726G>A variant (also known as p.A242A), located in coding exon 3 of the GAA gene, results from a G to A substitution at nucleotide position 726. This nucleotide substitution does not change the alanine at codon 242. This alteration has been reported in newborn screening programs for Pompe disease (Tang H et al. Int J Neonatal Screen, 2020 Mar;6:9; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6; Gragnaniello V et al. Mol Genet Metab Rep, 2022 Dec;33:100929; Burton BK et al. Int J Neonatal Screen, 2020 Mar;6:4). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	20
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148578399; hg19: chr17-78081389;