rs752851284
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000164139.4(PYGM):c.425-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
ENST00000164139.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.425-2A>G | splice_acceptor_variant | ENST00000164139.4 | NP_005600.1 | |||
PYGM | NM_001164716.1 | c.244-85A>G | intron_variant | NP_001158188.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.425-2A>G | splice_acceptor_variant | 1 | NM_005609.4 | ENSP00000164139 | P1 | |||
PYGM | ENST00000377432.7 | c.244-85A>G | intron_variant | 2 | ENSP00000366650 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251086Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135744
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461502Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727064
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 19, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2021 | 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with PYGM-related disease. ClinVar contains an entry for this variant (Variation ID: 370481). This variant is present in population databases (rs752851284, ExAC 0.002%). This sequence change affects an acceptor splice site in intron 3 of the PYGM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at