rs267606851
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000175.5(GPI):c.1028A>G(p.Gln343Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
GPI
NM_000175.5 missense
NM_000175.5 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 8.95
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000175.5
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
?
Variant 19-34394032-A-G is Pathogenic according to our data. Variant chr19-34394032-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13646.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPI | NM_000175.5 | c.1028A>G | p.Gln343Arg | missense_variant | 12/18 | ENST00000356487.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPI | ENST00000356487.11 | c.1028A>G | p.Gln343Arg | missense_variant | 12/18 | 1 | NM_000175.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250694Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135536
GnomAD3 exomes
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460834Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726798
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GnomAD4 genome ? Cov.: 32
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?
Cov.:
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Hemolytic anemia due to glucophosphate isomerase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 1996 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Pathogenic
Polyphen
1.0
.;.;D;D
Vest4
0.85
MutPred
0.89
.;.;Loss of catalytic residue at Q343 (P = 0.0845);Loss of catalytic residue at Q343 (P = 0.0845);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at