Variant X-154295948-G-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.89G>A(p.Arg30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,210,282 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000037 ( 0 hom. 12 hem. )

Consequence

TKTL1
NM_012253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3444724).

BS2

High Hemizygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TKTL1	NM_012253.4 linkuse as main transcript	c.89G>A	p.Arg30His	missense_variant	1/13	ENST00000369915.8	NP_036385.3	P51854-3
TKTL1	NM_001145933.2 linkuse as main transcript	c.89G>A	p.Arg30His	missense_variant	1/13		NP_001139405.1	B7Z7I0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TKTL1	ENST00000369915.8 linkuse as main transcript	c.89G>A	p.Arg30His	missense_variant	1/13	1	NM_012253.4	ENSP00000358931.3	P51854-3
TKTL1	ENST00000439635.5 linkuse as main transcript	n.89G>A		non_coding_transcript_exon_variant	1/5	4		ENSP00000399763.1	F8WF97
TKTL1	ENST00000710264.1 linkuse as main transcript	n.89G>A		non_coding_transcript_exon_variant	1/13			ENSP00000518160.1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112209

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34349

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

182593

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

67383

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000373

AC:

AN:

1098073

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

363431

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000439

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112209

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34349

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:

0.0000564

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Nov 17, 2022

The c.89G>A (p.R30H) alteration is located in exon 1 (coding exon 1) of the TKTL1 gene. This alteration results from a G to A substitution at nucleotide position 89, causing the arginine (R) at amino acid position 30 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.025

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.29

Sift

Benign

0.049

Sift4G

Uncertain

0.060

Polyphen

1.0

Vest4

0.46

MVP

0.33

MPC

0.15

ClinPred

0.24

GERP RS

4.5

Varity_R

0.39

gMVP

0.47

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