rs121964845

Positions:

chr12-6869174-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PP3_ModeratePP5_Very_StrongBS1_Supporting

The NM_000365.6(TPI1):c.315G>C(p.Glu105Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,110 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

TPI1
NM_000365.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.76

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 Pathogenic. Variant got 13 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, 0.872

PP5

Variant 12-6869174-G-C is Pathogenic according to our data. Variant chr12-6869174-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6869174-G-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000269 (393/1461876) while in subpopulation NFE AF= 0.000337 (375/1112006). AF 95% confidence interval is 0.000309. There are 0 homozygotes in gnomad4_exome. There are 200 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TPI1	NM_000365.6 linkuse as main transcript	c.315G>C	p.Glu105Asp	missense_variant	3/7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1 linkuse as main transcript	c.426G>C	p.Glu142Asp	missense_variant	3/7		NP_001152759.1
TPI1	NM_001258026.2 linkuse as main transcript	c.69G>C	p.Glu23Asp	missense_variant	3/7		NP_001244955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000396705.10 linkuse as main transcript	c.315G>C	p.Glu105Asp	missense_variant	3/7	1	NM_000365.6	ENSP00000379933	P1	P60174-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152234

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000755

AC:

AN:

251496

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135922

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:

0.000149

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000269

AC:

393

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

200

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000337

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000105

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74376

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:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Triosephosphate isomerase deficiency

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 17, 2018	The TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of clinical triosephosphate isomerase (TPI) deficiency. Across a selection of the available literature, the p.Glu105Asp variant was observed in 19 patients with TPI deficiency, including 13 homozygotes and six compound heterozygotes (Daar et al. 1986; Schneider et al. 1995; Arya et al. 1997; Linarello et al. 1998; Valentin et al. 2000; Yenicesu et al. 2000; Fermo et al. 2010; Sarper et al. 2013). Rodriguez-Almazan et al. (2008) demonstrated that the p.Glu105Asp variant results in instability of the TPI dimer and causes dissociation of the protein into inactive monomers, while De La Mora-De La Mora et al. (2013) showed that the p.Glu105Asp variant increases enzyme susceptibility to proteolysis. The highest allele frequency reported for this variant in the Exome Aggregation Consortium database is 0.000150 in the non-Finnish European population. Based on the collective evidence, the TPI1 p.Glu105Asp variant is classified as pathogenic for triosephosphate isomerase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 22, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2018	The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals w ith triosephosphate isomerase deficiency (Aissa 2014, Alabdullatif 2017, Arya 19 97, Daar 1986, Nolan 2016, Pekrun 1995, Sarper 2013, Valentin 2000). It has als o been identified in 0.015% (19/129206) of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). In vitro functional studies and computational pred iction tools support an impact on protein function (Daar 1986, Ralser 2006, De L a Mora-De La Mora 2013). In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive triosephosphate isomerase deficiency. AC MG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics Facility, Ludwig-Maximilians-Universität München	Dec 28, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPI1 function (PMID: 17183658). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12468). This missense change has been observed in individual(s) with triosephosphate isomerase deficiency (PMID: 2876430, 10910933, 24192681). This variant is present in population databases (rs121964845, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the TPI1 protein (p.Glu105Asp). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.87

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

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.0

M;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.9

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

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.012

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.97

Loss of disorder (P = 0.1679);Loss of disorder (P = 0.1679);.;.;.;.;.;.;

MVP

0.97

MPC

1.1

ClinPred

0.69

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.98

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