Variant X-154323333-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_012253.4(TKTL1):c.1313C>A(p.Ala438Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 1,209,305 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 131 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 0.00021 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00044 ( 0 hom. 127 hem. )

Consequence

TKTL1
NM_012253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27294028).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TKTL1	NM_012253.4 linkuse as main transcript	c.1313C>A	p.Ala438Asp	missense_variant	9/13	ENST00000369915.8	NP_036385.3
TKTL1	NM_001145933.2 linkuse as main transcript	c.1295C>A	p.Ala432Asp	missense_variant	9/13		NP_001139405.1
TKTL1	NM_001145934.2 linkuse as main transcript	c.1145C>A	p.Ala382Asp	missense_variant	8/12		NP_001139406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TKTL1	ENST00000369915.8 linkuse as main transcript	c.1313C>A	p.Ala438Asp	missense_variant	9/13	1	NM_012253.4	ENSP00000358931	P1	P51854-3
TKTL1	ENST00000369912.2 linkuse as main transcript	c.1145C>A	p.Ala382Asp	missense_variant	8/12	1		ENSP00000358928		P51854-4
TKTL1	ENST00000465168.1 linkuse as main transcript	n.504C>A		non_coding_transcript_exon_variant	3/4	4
TKTL1	ENST00000710264.1 linkuse as main transcript	c.1313C>A	p.Ala438Asp	missense_variant, NMD_transcript_variant	9/13			ENSP00000518160

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

111841

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

34011

show subpopulations

Gnomad AFR

AF:

0.0000977

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:

0.000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000990

AC:

AN:

181895

Hom.:

AF XY:

0.0000904

AC XY:

AN XY:

66379

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.0000369

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:

0.000184

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000436

AC:

478

AN:

1097464

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

127

AN XY:

362836

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000285

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:

0.000556

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000206

AC:

AN:

111841

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

34011

show subpopulations

Gnomad4 AFR

AF:

0.0000977

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:

0.000377

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

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 25, 2024

The c.1313C>A (p.A438D) alteration is located in exon 9 (coding exon 9) of the TKTL1 gene. This alteration results from a C to A substitution at nucleotide position 1313, causing the alanine (A) at amino acid position 438 to be replaced by an aspartic acid (D). 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

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.32

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.25

Sift

Benign

0.094

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.25

B;.

Vest4

0.46

MVP

0.52

MPC

0.13

ClinPred

0.052

GERP RS

1.4

Varity_R

0.34

gMVP

0.56

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