rs121964846
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The ENST00000396705.10(TPI1):c.367G>A(p.Gly123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,952 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
TPI1
ENST00000396705.10 missense
ENST00000396705.10 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 6.75
Genes affected
TPI1 (HGNC:12009): (triosephosphate isomerase 1) This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a chain Triosephosphate isomerase (size 247) in uniprot entity TPIS_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in ENST00000396705.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.832
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPI1 | NM_000365.6 | c.367G>A | p.Gly123Arg | missense_variant | 4/7 | ENST00000396705.10 | NP_000356.1 | |
TPI1 | NM_001159287.1 | c.478G>A | p.Gly160Arg | missense_variant | 4/7 | NP_001152759.1 | ||
TPI1 | NM_001258026.2 | c.121G>A | p.Gly41Arg | missense_variant | 4/7 | NP_001244955.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPI1 | ENST00000396705.10 | c.367G>A | p.Gly123Arg | missense_variant | 4/7 | 1 | NM_000365.6 | ENSP00000379933 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135882
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461760Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727190
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Triosephosphate isomerase manchester Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1992 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 123 of the TPI1 protein (p.Gly123Arg). This variant is present in population databases (rs121964846, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TPI1-related conditions. This variant is also known as p.Gly122Arg. ClinVar contains an entry for this variant (Variation ID: 12469). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TPI1 function (PMID: 1339398, 17183658). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;.;.;.;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;N;.;N;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;T;.;T;.;.
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
P;P;.;.;.;.;.
Vest4
MutPred
Loss of catalytic residue at V161 (P = 0.0232);Loss of catalytic residue at V161 (P = 0.0232);.;.;.;.;.;
MVP
MPC
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