X-154315269-T-C

Position:

• chrX-154315269-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_012253.4(TKTL1):​c.961T>C​(p.Phe321Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,097,962 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes 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: 0.000015 (0 hom. 8 hem.)
• Consequence: TKTL1 NM_012253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TKTL1	NM_012253.4	c.961T>C	p.Phe321Leu	missense_variant	7/13	ENST00000369915.8	NP_036385.3
TKTL1	NM_001145933.2	c.943T>C	p.Phe315Leu	missense_variant	7/13		NP_001139405.1
TKTL1	NM_001145934.2	c.793T>C	p.Phe265Leu	missense_variant	6/12		NP_001139406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TKTL1	ENST00000369915.8	c.961T>C	p.Phe321Leu	missense_variant	7/13	1	NM_012253.4	ENSP00000358931.3
TKTL1	ENST00000369912.2	c.793T>C	p.Phe265Leu	missense_variant	6/12	1		ENSP00000358928.2
TKTL1	ENST00000710264.1	n.961T>C		non_coding_transcript_exon_variant	7/13			ENSP00000518160.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097962 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 8 AN XY: 363320

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.961T>C (p.F321L) alteration is located in exon 7 (coding exon 7) of the TKTL1 gene. This alteration results from a T to C substitution at nucleotide position 961, causing the phenylalanine (F) at amino acid position 321 to be replaced by a leucine (L). 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	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.035	D;D
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.68		Gain of phosphorylation at Y318 (P = 0.2142);.;
MVP		0.89
MPC		0.22
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.61
gMVP		0.40

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

Other links and lift over

dbSNP: rs1179635832; hg19: chrX-153543619;