rs754285414

Positions:

• chr17-80104933-G-A
• chr17-80104933-G-C
• chr17-80104933-G-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.347G>A​(p.Gly116Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G116V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.39

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=0.13446614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.347G>A	p.Gly116Glu	missense_variant	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.347G>A	p.Gly116Glu	missense_variant	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 10, 2019

- -

Glycogen storage disease, type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2020

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function. This variant has not been reported in the literature in individuals with GAA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 116 of the GAA protein (p.Gly116Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.0010
DANN	Benign	0.42
DEOGEN2	Benign	0.16	T;.;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.24	T;T;.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.13	.;.;B;B
Vest4		0.11
MutPred		0.58		Loss of ubiquitination at K114 (P = 0.069);Loss of ubiquitination at K114 (P = 0.069);Loss of ubiquitination at K114 (P = 0.069);Loss of ubiquitination at K114 (P = 0.069);
MVP		0.65
MPC		0.14
ClinPred		0.053	T
GERP RS		-6.6
Varity_R		0.054
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78078732;