Variant X-154312711-C-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.802C>G(p.Pro268Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,209,591 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000042 ( 0 hom. 5 hem. )

Consequence

TKTL1
NM_012253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031393707).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TKTL1	NM_012253.4 linkuse as main transcript	c.802C>G	p.Pro268Ala	missense_variant	6/13	ENST00000369915.8	NP_036385.3	P51854-3
TKTL1	NM_001145933.2 linkuse as main transcript	c.784C>G	p.Pro262Ala	missense_variant	6/13		NP_001139405.1	B7Z7I0
TKTL1	NM_001145934.2 linkuse as main transcript	c.634C>G	p.Pro212Ala	missense_variant	5/12		NP_001139406.1	P51854-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TKTL1	ENST00000369915.8 linkuse as main transcript	c.802C>G	p.Pro268Ala	missense_variant	6/13	1	NM_012253.4	ENSP00000358931.3	P51854-3
TKTL1	ENST00000369912.2 linkuse as main transcript	c.634C>G	p.Pro212Ala	missense_variant	5/12	1		ENSP00000358928.2	P51854-4
TKTL1	ENST00000710264.1 linkuse as main transcript	n.802C>G		non_coding_transcript_exon_variant	6/13			ENSP00000518160.1

Frequencies

GnomAD3 genomes

AF:

0.000233

AC:

AN:

111580

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

33774

show subpopulations

Gnomad AFR

AF:

0.000849

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

GnomAD3 exomes

AF:

0.0000874

AC:

AN:

183064

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

67536

show subpopulations

Gnomad AFR exome

AF:

0.00114

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1097956

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363322

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000238

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000233

AC:

AN:

111635

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

33839

show subpopulations

Gnomad4 AFR

AF:

0.000847

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000298

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

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

Dec 20, 2023

The c.802C>G (p.P268A) alteration is located in exon 6 (coding exon 6) of the TKTL1 gene. This alteration results from a C to G substitution at nucleotide position 802, causing the proline (P) at amino acid position 268 to be replaced by an alanine (A). 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

0.083

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.77

D;.

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Benign

0.11

Sift

Benign

0.058

T;D

Sift4G

Benign

0.082

T;T

Polyphen

0.13

B;.

Vest4

0.094

MVP

0.37

MPC

0.076

ClinPred

0.068

GERP RS

4.5

Varity_R

0.29

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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