chr12-48139349-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_000289.6(PFKM):c.1127G>A(p.Arg376Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000434 in 1,611,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000289.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PFKM | NM_000289.6 | c.1127G>A | p.Arg376Gln | missense_variant, splice_region_variant | 12/23 | ENST00000359794.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PFKM | ENST00000359794.11 | c.1127G>A | p.Arg376Gln | missense_variant, splice_region_variant | 12/23 | 1 | NM_000289.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251252Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135790
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459638Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2AN XY: 726310
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74462
ClinVar
Submissions by phenotype
Glycogen storage disease, type VII Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 376 of the PFKM protein (p.Arg376Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs187131358, gnomAD 0.006%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 8659544). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554445). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site within intron 12 and introduces a premature termination codon (PMID: 8659544). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2022 | Variant summary: PFKM c.1127G>A (p.Arg376Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. As the variant alters the last conserved nucleotide of exon 12 adjacent to the canonical intron 12 splicing donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to the retention of 155 nucleotides of the intronic sequence (example, Nichols_1996). This is predicted to result in premature termination of translation. The variant allele was found at a frequency of 1.2e-05 in 251252 control chromosomes. c.1127G>A has been reported in the literature as a compound heterozygous genotype in four individuals affected with Glycogen Storage Disease, Type VII (Tarui disease) in a Swedish family (example, Nichols_1996). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at