X-154305383-C-G

Position:

• chrX-154305383-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000369915.8(TKTL1):​c.214C>G​(p.Pro72Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TKTL1 ENST00000369915.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TKTL1	NM_012253.4	c.214C>G	p.Pro72Ala	missense_variant	2/13	ENST00000369915.8	NP_036385.3
TKTL1	NM_001145933.2	c.196C>G	p.Pro66Ala	missense_variant	2/13		NP_001139405.1
TKTL1	NM_001145934.2	c.46C>G	p.Pro16Ala	missense_variant	1/12		NP_001139406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TKTL1	ENST00000369915.8	c.214C>G	p.Pro72Ala	missense_variant	2/13	1	NM_012253.4	ENSP00000358931.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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

Apr 17, 2024

The c.214C>G (p.P72A) alteration is located in exon 2 (coding exon 2) of the TKTL1 gene. This alteration results from a C to G substitution at nucleotide position 214, causing the proline (P) at amino acid position 72 to be replaced by an alanine (A). 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	0.084
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Uncertain	0.43	T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.48
MutPred		0.80		Loss of ubiquitination at K68 (P = 0.0613);Loss of ubiquitination at K68 (P = 0.0613);.;
MVP		0.41
MPC		0.30
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.45
gMVP		0.71

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.

Other links and lift over

hg19: chrX-153533735;