chr19-34366798-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_000175.5(GPI):c.229G>A(p.Val77Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,260 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 1 hom. )
Consequence
GPI
NM_000175.5 missense
NM_000175.5 missense
Scores
4
6
3
Clinical Significance
Conservation
PhyloP100: 4.46
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 Likely_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000438 (64/1460968) while in subpopulation EAS AF= 0.00126 (50/39700). AF 95% confidence interval is 0.000981. There are 1 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAdExome at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPI | NM_000175.5 | c.229G>A | p.Val77Met | missense_variant | 3/18 | ENST00000356487.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPI | ENST00000356487.11 | c.229G>A | p.Val77Met | missense_variant | 3/18 | 1 | NM_000175.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251402Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135916
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1460968Hom.: 1 Cov.: 30 AF XY: 0.0000427 AC XY: 31AN XY: 726824
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2022 | The c.229G>A (p.V77M) alteration is located in exon 3 (coding exon 3) of the GPI gene. This alteration results from a G to A substitution at nucleotide position 229, causing the valine (V) at amino acid position 77 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;.;.;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
Polyphen
1.0
.;.;.;.;.;.;.;D;.;.;.;D
Vest4
0.55, 0.56
MutPred
0.70
.;.;.;.;.;.;Loss of catalytic residue at V77 (P = 0.0012);Loss of catalytic residue at V77 (P = 0.0012);Loss of catalytic residue at V77 (P = 0.0012);Loss of catalytic residue at V77 (P = 0.0012);Loss of catalytic residue at V77 (P = 0.0012);Loss of catalytic residue at V77 (P = 0.0012);
MVP
0.97
MPC
1.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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