12-6867486-C-T

Position:

chr12-6867486-C-T

Variant summary

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

The ENST00000229270.8(TPI1):c.31C>T(p.His11Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,544,326 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

TPI1
ENST00000229270.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.675

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 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=0.003624767).

BP6

Variant 12-6867486-C-T is Benign according to our data. Variant chr12-6867486-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 994232.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00194 (295/152228) while in subpopulation AMR AF= 0.0081 (124/15306). AF 95% confidence interval is 0.00694. There are 0 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPI1	NM_001159287.1 linkuse as main transcript	c.31C>T	p.His11Tyr	missense_variant	1/7		NP_001152759.1
TPI1	NM_000365.6 linkuse as main transcript			upstream_gene_variant		ENST00000396705.10	NP_000356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000229270.8 linkuse as main transcript	c.31C>T	p.His11Tyr	missense_variant	1/7	1		ENSP00000229270		P60174-3
TPI1	ENST00000613953.4 linkuse as main transcript	c.31C>T	p.His11Tyr	missense_variant	1/7	1		ENSP00000484435		P60174-3
TPI1	ENST00000396705.10 linkuse as main transcript			upstream_gene_variant		1	NM_000365.6	ENSP00000379933	P1	P60174-1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

295

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00811

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00141

AC:

221

AN:

156968

Hom.:

AF XY:

0.00145

AC XY:

123

AN XY:

84734

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.00265

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000607

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00177

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00133

AC:

1858

AN:

1392098

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

899

AN XY:

685718

show subpopulations

Gnomad4 AFR exome

AF:

0.000226

Gnomad4 AMR exome

AF:

0.00259

Gnomad4 ASJ exome

AF:

0.00277

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000656

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.00135

GnomAD4 genome

AF:

0.00194

AC:

295

AN:

152228

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

147

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00214

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000805

AC:

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TPI1: BP4 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Triosephosphate isomerase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.6

DANN

Benign

0.96

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

PROVEAN

Benign

0.0

N;.

REVEL

Benign

0.013

Sift

Benign

0.10

T;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.10

MVP

0.043

MPC

0.44

ClinPred

0.0050

GERP RS

-2.4

Varity_R

0.049

gMVP

0.26

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