rs770610356
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate
The NM_000152.5(GAA):c.1309C>A(p.Arg437Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GAA
NM_000152.5 missense
NM_000152.5 missense
Scores
7
4
7
Clinical Significance
Conservation
PhyloP100: 1.49
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 Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000152.5
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-80108811-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 189082.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
?
Variant 17-80108811-C-A is Pathogenic according to our data. Variant chr17-80108811-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2155070.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1309C>A | p.Arg437Ser | missense_variant | 8/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1309C>A | p.Arg437Ser | missense_variant | 8/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1445942Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 718184
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1445942
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
718184
Gnomad4 AFR exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg437 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12601120, 17805474, 29124014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 437 of the GAA protein (p.Arg437Ser). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MutPred
Gain of phosphorylation at R437 (P = 0.0809);Gain of phosphorylation at R437 (P = 0.0809);
MVP
MPC
0.20
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