ENST00000229270.8:c.50T>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

The ENST00000229270.8(TPI1):c.50T>G(p.Ile17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,579,330 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0029 ( 11 hom. )

Consequence

TPI1
ENST00000229270.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.12

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 Benign. Variant got -7 ACMG points.

PM1

In a chain Triosephosphate isomerase (size 247) in uniprot entity TPIS_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in ENST00000229270.8

BP4

Computational evidence support a benign effect (MetaRNN=0.008082598).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00377 (573/152082) while in subpopulation AFR AF= 0.00755 (313/41482). AF 95% confidence interval is 0.00686. There are 2 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_001159287.1 link	c.50T>G	p.Ile17Arg	missense_variant	Exon 1 of 7		NP_001152759.1	P60174-3
TPI1	NM_000365.6 link	c.-62T>G		upstream_gene_variant		ENST00000396705.10	NP_000356.1	P60174-1V9HWK1Q53HE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPI1	ENST00000229270.8 link	c.50T>G	p.Ile17Arg	missense_variant	Exon 1 of 7	1		ENSP00000229270.4	P60174-3
TPI1	ENST00000613953.4 link	c.50T>G	p.Ile17Arg	missense_variant	Exon 1 of 7	1		ENSP00000484435.1	P60174-3
TPI1	ENST00000396705.10 link	c.-62T>G		upstream_gene_variant		1	NM_000365.6	ENSP00000379933.4	P60174-1

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

576

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00754

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00210

AC:

405

AN:

193188

Hom.:

AF XY:

0.00218

AC XY:

230

AN XY:

105348

show subpopulations

Gnomad AFR exome

AF:

0.00611

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00236

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.000389

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00461

GnomAD4 exome

AF:

0.00291

AC:

4160

AN:

1427248

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2111

AN XY:

707182

show subpopulations

Gnomad4 AFR exome

AF:

0.00766

Gnomad4 AMR exome

AF:

0.00278

Gnomad4 ASJ exome

AF:

0.00334

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00144

Gnomad4 FIN exome

AF:

0.000481

Gnomad4 NFE exome

AF:

0.00299

Gnomad4 OTH exome

AF:

0.00381

GnomAD4 genome

AF:

0.00377

AC:

573

AN:

152082

Hom.:

Cov.:

AF XY:

0.00362

AC XY:

269

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00755

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.00262

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.00410

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00219

AC:

262

Asia WGS

AF:

0.00260

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Oct 18, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPI1: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Triosephosphate isomerase deficiency

Uncertain:1

Jan 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

0.082

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.51

.;T

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N

PROVEAN

Benign

-0.14

N;.

REVEL

Benign

0.21

Sift

Benign

0.16

T;.

Sift4G

Benign

0.11

T;T

Vest4

0.51

MVP

0.32

MPC

1.6

ClinPred

0.096

GERP RS

4.8

Varity_R

0.21

gMVP

0.37

Splicing

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