rs786204467
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000152.5(GAA):āc.1A>Gā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 6.9e-7 ( 0 hom. )
Consequence
GAA
NM_000152.5 start_lost
NM_000152.5 start_lost
Scores
6
3
7
Clinical Significance
Conservation
PhyloP100: 1.38
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 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000152.5 (GAA) was described as [Likely_pathogenic] in ClinVar as 984798
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-80104587-A-G is Pathogenic according to our data. Variant chr17-80104587-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80104587-A-G is described in Lovd as [Pathogenic]. Variant chr17-80104587-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1A>G | p.Met1? | start_lost | 2/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1A>G | p.Met1? | start_lost | 2/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457632Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 724840
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74284
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 08, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 15, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jun 22, 2023 | The homozygous start loss variant c.1A>G (p.Met1?) has been identified in a proband with muscle weakness and hypotonia, . This variant has not been found in gnomAD (aggregated) database. This has been previously reported PMID: 18429042 This homozygous variant start loss variant c.1A>G (p.Met1?) has been identified in 6 more patient and in 4 patient in heterozygous state. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 05, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys103 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1109266, 14695532, 18429042, 18607768, 24158270, 29181627). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 188785). Disruption of the initiator codon has been observed in individuals with Pompe disease (PMID: 22252923, 29124014, 29422078). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PROVEAN
Benign
.;.;N;N
REVEL
Uncertain
Sift
Pathogenic
.;.;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
0.0050
.;.;B;B
Vest4
0.85
MutPred
Gain of methylation at R4 (P = 0.2438);Gain of methylation at R4 (P = 0.2438);Gain of methylation at R4 (P = 0.2438);Gain of methylation at R4 (P = 0.2438);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at