11-763456-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_006755.2(TALDO1):c.574C>T(p.Arg192Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

TALDO1
NM_006755.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.79

Publications

12 publications found

Variant links:

Genes affected

TALDO1 (HGNC:11559): (transaldolase 1) Transaldolase 1 is a key enzyme of the nonoxidative pentose phosphate pathway providing ribose-5-phosphate for nucleic acid synthesis and NADPH for lipid biosynthesis. This pathway can also maintain glutathione at a reduced state and thus protect sulfhydryl groups and cellular integrity from oxygen radicals. The functional gene of transaldolase 1 is located on chromosome 11 and a pseudogene is identified on chromosome 1 but there are conflicting map locations. The second and third exon of this gene were developed by insertion of a retrotransposable element. This gene is thought to be involved in multiple sclerosis. [provided by RefSeq, Jul 2008]

TALDO1 Gene-Disease associations (from GenCC):

transaldolase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

TALDO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-763457-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 420180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 11-763456-C-T is Pathogenic according to our data. Variant chr11-763456-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 381759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TALDO1	NM_006755.2 link	c.574C>T	p.Arg192Cys	missense_variant	Exon 5 of 8	ENST00000319006.8	NP_006746.1	P37837-1A0A140VK56

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TALDO1	ENST00000319006.8 link	c.574C>T	p.Arg192Cys	missense_variant	Exon 5 of 8	1	NM_006755.2	ENSP00000321259.3		P37837-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251442

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1112002

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151538

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73952

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41148

American (AMR)

AF:

0.00

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67904

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of transaldolase

Pathogenic:3

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM3(very strong),PM2,PM5,PP3 -

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:2

Aug 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the TALDO1 protein (p.Arg192Cys). This variant is present in population databases (rs751425603, gnomAD 0.01%). This missense change has been observed in individual(s) with transaldolase deficiency (PMID: 18331807, 25388407). ClinVar contains an entry for this variant (Variation ID: 381759). 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 disruptive. This variant disrupts the p.Arg192 amino acid residue in TALDO1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15877206, 24497183, 29292491). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Mar 19, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18331807, 25388407, 27391121, 23315216, 27130472, 35186000, 30740741, 32828637, 37071763, 34677006, 31769880) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

H;.

PhyloP100

3.8

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.98

MutPred

0.98

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

1.0

MPC

0.29

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.84

gMVP

0.97

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over