12-6867538-C-G

Position:

chr12-6867538-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The ENST00000229270.8(TPI1):c.83C>G(p.Thr28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,608,602 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T28I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00056 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00087 ( 12 hom. )

Consequence

TPI1
ENST00000229270.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.03

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 -11 ACMG points.

PM1

In a chain Triosephosphate isomerase (size 247) in uniprot entity TPIS_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in ENST00000229270.8

BP4

Computational evidence support a benign effect (MetaRNN=0.004826635).

BP6

Variant 12-6867538-C-G is Benign according to our data. Variant chr12-6867538-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330976.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000558 (85/152332) while in subpopulation SAS AF= 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 1 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPI1	NM_000365.6 linkuse as main transcript	c.-29C>G		5_prime_UTR_variant	1/7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1 linkuse as main transcript	c.83C>G	p.Thr28Ser	missense_variant	1/7		NP_001152759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000229270.8 linkuse as main transcript	c.83C>G	p.Thr28Ser	missense_variant	1/7	1		ENSP00000229270		P60174-3
TPI1	ENST00000613953.4 linkuse as main transcript	c.83C>G	p.Thr28Ser	missense_variant	1/7	1		ENSP00000484435		P60174-3
TPI1	ENST00000396705.10 linkuse as main transcript	c.-29C>G		5_prime_UTR_variant	1/7	1	NM_000365.6	ENSP00000379933	P1	P60174-1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00159

AC:

377

AN:

236626

Hom.:

AF XY:

0.00197

AC XY:

256

AN XY:

129852

show subpopulations

Gnomad AFR exome

AF:

0.000145

Gnomad AMR exome

AF:

0.000300

Gnomad ASJ exome

AF:

0.00185

Gnomad EAS exome

AF:

0.0000568

Gnomad SAS exome

AF:

0.00884

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000700

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.000866

AC:

1261

AN:

1456270

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

795

AN XY:

724190

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.00135

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00805

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000411

Gnomad4 OTH exome

AF:

0.000898

GnomAD4 genome

AF:

0.000558

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000359

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TPI1: BP4, BS2 -

Triosephosphate isomerase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.26

.;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

-0.020

N;.

REVEL

Benign

0.019

Sift

Benign

0.62

T;.

Sift4G

Benign

0.72

T;T

Vest4

0.039

MutPred

0.17

Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);

MVP

0.12

MPC

0.34

ClinPred

0.0098

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.086

gMVP

0.17

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