12-48131394-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000289.6(PFKM):c.237+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000728 in 1,606,674 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
NM_000289.6 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PFKM | NM_000289.6 | c.237+1G>A | splice_donor_variant | ENST00000359794.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PFKM | ENST00000359794.11 | c.237+1G>A | splice_donor_variant | 1 | NM_000289.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251386Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135872
GnomAD4 exome AF: 0.0000743 AC: 108AN: 1454540Hom.: 0 Cov.: 28 AF XY: 0.0000884 AC XY: 64AN XY: 724204
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74338
ClinVar
Submissions by phenotype
Glycogen storage disease, type VII Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | NM_001166686.1(PFKM):c.450+1G>A is a canonical splice variant classified as pathogenic in the context of glycogen storage disease type VII. c.450+1G>A has been observed in cases with relevant disease (PMID: 8037209). Functional assessments of this variant are not available in the literature. c.450+1G>A has been observed in population frequency databases (gnomAD: ASJ 0.24%). In summary, NM_001166686.1(PFKM):c.450+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 15, 2014 | The 237+1G>A variant in PFKM has been previously identified in one homozygous patient with glycogen storage disease 7 and was found to segregate with disease in an affected homozygous relative (Raben 1993). This variant is located in the 5' splice region and computational tools do suggest an impact to splicing. In summary, this variant meets our criteria for pathogenicity. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 28, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change affects a donor splice site in intron 4 of the PFKM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs202143236, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with phosphofructokinase deficiency (PMID: 8037209, 8444874, 28779239). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189239). Studies have shown that disruption of this splice site results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 8444874). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 06, 2022 | - - |
Rhabdomyolysis Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 05, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 28779239, 28627441, 8444874, 25525159, 31589614, 31653659) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at