rs951742543

Positions:

• chr17-80118308-A-C
• chr17-80118308-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000152.5(GAA):​c.2597A>C​(p.Glu866Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,438,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.0200

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.11097106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2597A>C	p.Glu866Ala	missense_variant	18/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2597A>C	p.Glu866Ala	missense_variant	18/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000426 AC: 1 AN: 234558 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1438624 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 712754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2021	This sequence change replaces glutamic acid with alanine at codon 866 of the GAA protein (p.Glu866Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GAA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 13, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 25, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2023

The p.E866A variant (also known as c.2597A>C), located in coding exon 17 of the GAA gene, results from an A to C substitution at nucleotide position 2597. The glutamic acid at codon 866 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.3
DANN	Benign	0.90
DEOGEN2	Uncertain	0.46	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.54	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.14
Sift	Benign	0.13	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;B
Vest4		0.086
MutPred		0.42		Loss of disorder (P = 0.0913);Loss of disorder (P = 0.0913);
MVP		0.79
MPC		0.12
ClinPred		0.022	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.79

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: rs951742543; hg19: chr17-78092107;