rs755117847
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005609.4(PYGM):βc.78_79delβ(p.Glu27AlafsTer50) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000558 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
PYGM
NM_005609.4 frameshift
NM_005609.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.97
Genes affected
PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 262 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-64759819-TCA-T is Pathogenic according to our data. Variant chr11-64759819-TCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64759819-TCA-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.78_79del | p.Glu27AlafsTer50 | frameshift_variant | 1/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.78_79del | p.Glu27AlafsTer50 | frameshift_variant | 1/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.78_79del | p.Glu27AlafsTer50 | frameshift_variant | 1/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.78_79del | p.Glu27AlafsTer50 | frameshift_variant | 1/18 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251480Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461882Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727238
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74328
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 20, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 13, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188778). This variant is also known as T25fs. This premature translational stop signal has been observed in individual(s) with PYGM-related conditions (PMID: 15979037). This variant is present in population databases (rs755117847, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu27Alafs*50) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18067156, 19670320, 15979037, 29926259, 29143597, 21802952, 17404776, 16786513, 32528171) - |
Computational scores
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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