19-34366810-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000175.5(GPI):c.244del(p.Glu82SerfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GPI
NM_000175.5 frameshift
NM_000175.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.46
Genes affected
GPI (HGNC:4458): (glucose-6-phosphate isomerase) This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme (glucose-6-phosphate isomerase) that interconverts glucose-6-phosphate and fructose-6-phosphate. Extracellularly, the encoded protein (also referred to as neuroleukin) functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-34366810-CG-C is Pathogenic according to our data. Variant chr19-34366810-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1323032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPI | NM_000175.5 | c.244del | p.Glu82SerfsTer32 | frameshift_variant | 3/18 | ENST00000356487.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPI | ENST00000356487.11 | c.244del | p.Glu82SerfsTer32 | frameshift_variant | 3/18 | 1 | NM_000175.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251406Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461298Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726978
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hemolytic anemia due to glucophosphate isomerase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 26, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 21, 2022 | This sequence change creates a premature translational stop signal (p.Glu82Serfs*32) in the GPI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPI are known to be pathogenic (PMID: 10916680, 27519939). This variant is present in population databases (rs769026153, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GPI-related conditions. ClinVar contains an entry for this variant (Variation ID: 1323032). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at