rs121964846

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

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.75
Variant links:
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]

Genome browser will be placed here

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
TPI1NM_000365.6 linkuse as main transcriptc.367G>A p.Gly123Arg missense_variant 4/7 ENST00000396705.10 NP_000356.1
TPI1NM_001159287.1 linkuse as main transcriptc.478G>A p.Gly160Arg missense_variant 4/7 NP_001152759.1
TPI1NM_001258026.2 linkuse as main transcriptc.121G>A p.Gly41Arg missense_variant 4/7 NP_001244955.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPI1ENST00000396705.10 linkuse as main transcriptc.367G>A p.Gly123Arg missense_variant 4/71 NM_000365.6 ENSP00000379933 P1P60174-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251410
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461760
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

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 providedliterature onlyOMIMMar 01, 1992- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2022This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.64
D;D;.;.;.;.;T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
.;D;D;.;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.17
D
MutationAssessor
Benign
0.10
N;N;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-0.39
N;.;N;.;N;.;.
REVEL
Pathogenic
0.67
Sift
Uncertain
0.027
D;.;T;.;T;.;.
Sift4G
Benign
0.17
T;T;T;T;T;T;T
Polyphen
0.93
P;P;.;.;.;.;.
Vest4
0.93
MutPred
0.74
Loss of catalytic residue at V161 (P = 0.0232);Loss of catalytic residue at V161 (P = 0.0232);.;.;.;.;.;
MVP
0.88
MPC
1.3
ClinPred
0.70
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121964846; hg19: chr12-6978464; API