Variant X-154320778-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012253.4(TKTL1):c.1051G>A(p.Ala351Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

TKTL1
NM_012253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.05

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_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TKTL1	NM_012253.4 linkuse as main transcript	c.1051G>A	p.Ala351Thr	missense_variant	8/13	ENST00000369915.8	NP_036385.3
TKTL1	NM_001145933.2 linkuse as main transcript	c.1033G>A	p.Ala345Thr	missense_variant	8/13		NP_001139405.1
TKTL1	NM_001145934.2 linkuse as main transcript	c.883G>A	p.Ala295Thr	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.1051G>A	p.Ala351Thr	missense_variant	8/13	1	NM_012253.4	ENSP00000358931	P1	P51854-3
TKTL1	ENST00000369912.2 linkuse as main transcript	c.883G>A	p.Ala295Thr	missense_variant	7/12	1		ENSP00000358928		P51854-4
TKTL1	ENST00000465168.1 linkuse as main transcript	n.242G>A		non_coding_transcript_exon_variant	2/4	4
TKTL1	ENST00000710264.1 linkuse as main transcript	c.1051G>A	p.Ala351Thr	missense_variant, NMD_transcript_variant	8/13			ENSP00000518160

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097879

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363245

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

May 14, 2024

The c.1051G>A (p.A351T) alteration is located in exon 8 (coding exon 8) of the TKTL1 gene. This alteration results from a G to A substitution at nucleotide position 1051, causing the alanine (A) at amino acid position 351 to be replaced by a threonine (T). 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

0.082

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.1

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.52

Sift

Benign

0.10

T;T

Sift4G

Benign

0.083

T;T

Polyphen

0.68

P;.

Vest4

0.42

MutPred

0.91

Gain of phosphorylation at A351 (P = 0.1548);.;

MVP

0.90

MPC

0.20

ClinPred

0.89

GERP RS

1.9

Varity_R

0.17

gMVP

0.39

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over