rs267606993
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_005609.4(PYGM):c.1A>T(p.Met1?) variant causes a start lost change. 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
PYGM
NM_005609.4 start_lost
NM_005609.4 start_lost
Scores
6
5
4
Clinical Significance
Conservation
PhyloP100: 5.93
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_005609.4 (PYGM) was described as [Pathogenic] in ClinVar as 156341
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-64759898-T-A is Pathogenic according to our data. Variant chr11-64759898-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 553271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.1A>T | p.Met1? | start_lost | 1/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.1A>T | p.Met1? | start_lost | 1/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.1A>T | p.Met1? | start_lost | 1/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.1A>T | p.Met1? | start_lost | 1/18 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 10, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2022 | This sequence change affects the initiator methionine of the PYGM mRNA. The next in-frame methionine is located at codon 92. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with McArdle disease (PMID: 7951262, 9506549, 25740218, 28967462). ClinVar contains an entry for this variant (Variation ID: 553271). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
1.0
.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);
MVP
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