rs121964846

Positions:

chr12-6869300-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000365.6(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
NM_000365.6 missense

Scores

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]

TPI1 links:

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 4 pathogenic changes around while only 0 benign (100%) in NM_000365.6

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 linkuse as main transcript	c.367G>A	p.Gly123Arg	missense_variant	4/7	ENST00000396705.10	NP_000356.1	P60174-1V9HWK1Q53HE2
TPI1	NM_001159287.1 linkuse as main transcript	c.478G>A	p.Gly160Arg	missense_variant	4/7		NP_001152759.1	P60174-3
TPI1	NM_001258026.2 linkuse as main transcript	c.121G>A	p.Gly41Arg	missense_variant	4/7		NP_001244955.1	P60174-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000396705.10 linkuse as main transcript	c.367G>A	p.Gly123Arg	missense_variant	4/7	1	NM_000365.6	ENSP00000379933.4		P60174-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

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:

AN:

251410

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

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:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

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

LIST_S2

Uncertain

0.88

.;D;D;.;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.10

N;N;.;.;.;.;.

PrimateAI

Pathogenic

0.92

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over