Variant X-154310858-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_012253.4(TKTL1):c.373A>G(p.Ser125Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,209,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

TKTL1
NM_012253.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.64

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=0.06949088).

BP6

Variant X-154310858-A-G is Benign according to our data. Variant chrX-154310858-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2459762.Status of the report is criteria_provided_single_submitter, 1 stars.

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.373A>G	p.Ser125Gly	missense_variant	4/13	ENST00000369915.8	NP_036385.3
TKTL1	NM_001145933.2 linkuse as main transcript	c.355A>G	p.Ser119Gly	missense_variant	4/13		NP_001139405.1
TKTL1	NM_001145934.2 linkuse as main transcript	c.205A>G	p.Ser69Gly	missense_variant	3/12		NP_001139406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TKTL1	ENST00000369915.8 linkuse as main transcript	c.373A>G	p.Ser125Gly	missense_variant	4/13	1	NM_012253.4	ENSP00000358931	P1	P51854-3

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111785

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33959

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000476

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:

0.0000604

AC:

AN:

181989

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

66559

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000403

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097398

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000284

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:

0.0000217

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111785

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33959

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000476

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:

0.0000340

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.6

DANN

Benign

0.37

DEOGEN2

Benign

0.16

T;T;.

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.069

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.5

N;.;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

4.9

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.42

MutPred

0.59

Gain of catalytic residue at S125 (P = 0.054);Gain of catalytic residue at S125 (P = 0.054);.;

MVP

0.21

MPC

0.053

ClinPred

0.056

GERP RS

2.5

Varity_R

0.084

gMVP

0.87

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