rs1555599660
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000152.5(GAA):c.787C>T(p.His263Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H263H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
GAA
NM_000152.5 missense
NM_000152.5 missense
Scores
6
5
4
Clinical Significance
Conservation
PhyloP100: 7.79
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000152.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.854
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.787C>T | p.His263Tyr | missense_variant | 4/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.787C>T | p.His263Tyr | missense_variant | 4/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 06, 2017 | This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GAA-related disease. This sequence change replaces histidine with tyrosine at codon 263 of the GAA protein (p.His263Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.69, 0.69
MutPred
Gain of phosphorylation at H263 (P = 0.1565);Gain of phosphorylation at H263 (P = 0.1565);Gain of phosphorylation at H263 (P = 0.1565);
MVP
MPC
0.56
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at