Variant 12-6867669-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000365.6(TPI1):c.103C>G(p.Pro35Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TPI1
NM_000365.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.23612604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPI1	NM_000365.6 linkuse as main transcript	c.103C>G	p.Pro35Ala	missense_variant	1/7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1 linkuse as main transcript	c.214C>G	p.Pro72Ala	missense_variant	1/7		NP_001152759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000396705.10 linkuse as main transcript	c.103C>G	p.Pro35Ala	missense_variant	1/7	1	NM_000365.6	ENSP00000379933	P1	P60174-1
TPI1	ENST00000229270.8 linkuse as main transcript	c.214C>G	p.Pro72Ala	missense_variant	1/7	1		ENSP00000229270		P60174-3
TPI1	ENST00000613953.4 linkuse as main transcript	c.214C>G	p.Pro72Ala	missense_variant	1/7	1		ENSP00000484435		P60174-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000832

AC:

AN:

240378

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000589

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457084

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000450

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with TPI1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 35 of the TPI1 protein (p.Pro35Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Pathogenic

0.84

D;D;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.1

L;L;.

MutationTaster

Benign

0.88

N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.9

N;.;N

REVEL

Benign

0.20

Sift

Benign

0.21

T;.;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.011

B;B;.

Vest4

0.16

MutPred

0.28

Gain of ubiquitination at K70 (P = 0.0619);Gain of ubiquitination at K70 (P = 0.0619);.;

MVP

0.58

MPC

0.39

ClinPred

0.15

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.34

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