Variant X-154320796-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012253.4(TKTL1):c.1069A>G(p.Ile357Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000703 in 1,209,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000074 ( 0 hom. 21 hem. )

Consequence

TKTL1
NM_012253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.941

Variant links:

Genes affected

TKTL1 (HGNC:11835): (transketolase like 1) The protein encoded by this gene is a transketolase that acts as a homodimer and catalyzes the conversion of sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate to D-ribose 5-phosphate and D-xylulose 5-phosphate. This reaction links the pentose phosphate pathway with the glycolytic pathway. Variations in this gene may be the cause of Wernicke-Korsakoff syndrome. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

TKTL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056166172).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TKTL1	NM_012253.4 linkuse as main transcript	c.1069A>G	p.Ile357Val	missense_variant	8/13	ENST00000369915.8	NP_036385.3
TKTL1	NM_001145933.2 linkuse as main transcript	c.1051A>G	p.Ile351Val	missense_variant	8/13		NP_001139405.1
TKTL1	NM_001145934.2 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	7/12		NP_001139406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TKTL1	ENST00000369915.8 linkuse as main transcript	c.1069A>G	p.Ile357Val	missense_variant	8/13	1	NM_012253.4	ENSP00000358931	P1	P51854-3
TKTL1	ENST00000369912.2 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	7/12	1		ENSP00000358928		P51854-4
TKTL1	ENST00000465168.1 linkuse as main transcript	n.260A>G		non_coding_transcript_exon_variant	2/4	4
TKTL1	ENST00000710264.1 linkuse as main transcript	c.1069A>G	p.Ile357Val	missense_variant, NMD_transcript_variant	8/13			ENSP00000518160

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111662

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33848

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:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000272

AC:

AN:

183493

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67921

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

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:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000738

AC:

AN:

1097914

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

363268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000927

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111662

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33848

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:

0.0000754

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.1069A>G (p.I357V) alteration is located in exon 8 (coding exon 8) of the TKTL1 gene. This alteration results from a A to G substitution at nucleotide position 1069, causing the isoleucine (I) at amino acid position 357 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.27

DANN

Benign

0.18

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.28

N;.

MutationTaster

Benign

0.60

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.24

N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;.

Vest4

0.15

MVP

0.35

MPC

0.053

ClinPred

0.011

GERP RS

-0.56

Varity_R

0.035

gMVP

0.11

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