rs1555598609

Positions:

• chr17-80104734-G-A
• chr17-80104734-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.148G>A​(p.Glu50Lys) 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. 15/21 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)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.359

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=0.10119942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.148G>A	p.Glu50Lys	missense_variant	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.148G>A	p.Glu50Lys	missense_variant	2/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	GAA NM_000152.4 exon 2 p.Glu50Lys (c.148G>A): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:456382). This variant amino acid Lysine (Lys) is present in multiple species including the marmoset and the squirrel monkey, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 04, 2021	In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GAA-related disease. This sequence change replaces glutamic acid with lysine at codon 50 of the GAA protein (p.Glu50Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	4.2
DANN	Benign	0.96
DEOGEN2	Benign	0.0087	T;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.50	T;T;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.34	.;.;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.34	.;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.11	.;.;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0	.;.;B;B
Vest4		0.12, 0.12
MutPred		0.27		Gain of ubiquitination at E50 (P = 0.0025);Gain of ubiquitination at E50 (P = 0.0025);Gain of ubiquitination at E50 (P = 0.0025);Gain of ubiquitination at E50 (P = 0.0025);
MVP		0.82
MPC		0.12
ClinPred		0.055	T
GERP RS		-0.013
Varity_R		0.049
gMVP		0.54

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: rs1555598609; hg19: chr17-78078533;