rs546463058

chr17-80113229-G-Achr17-80113229-G-Cchr17-80113229-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000152.5(GAA):c.2052G>A(p.Pro684=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000581 in 1,600,714 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P684P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -7.38

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-80113229-G-A is Benign according to our data. Variant chr17-80113229-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387758.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-7.38 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2052G>A	p.Pro684=	synonymous_variant	15/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2052G>A	p.Pro684=	synonymous_variant	15/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000933 AC: 21 AN: 225086 Hom.: 0 AF XY: 0.000115 AC XY: 14 AN XY: 122242

Gnomad AFR exome AF: 0.000216

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000589

Gnomad SAS exome AF: 0.0000715

Gnomad FIN exome AF: 0.0000567

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000483 AC: 70 AN: 1448360 Hom.: 0 Cov.: 34 AF XY: 0.0000500 AC XY: 36 AN XY: 719584

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000162

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.0000397

Gnomad4 NFE exome AF: 0.0000425

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74494

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000227

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type II Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 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.2052G>A (p.Pro684=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by Invitae and GeneDx in ClinVar (Variation ID: 387758). This variant has been identified in 0.015% (5/33352) of Latino chromosomes and 0.013% (3/22566) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs546463058). 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: PM2, BP4, BP7 (Richards 2015). -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 18, 2020	- -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	GAA: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

This alteration is classified as likely 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	-0.88
Cadd	Benign	0.26
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs546463058; hg19: chr17-78087028; COSMIC: COSV56411934; COSMIC: COSV56411934;