chr4-163472568-A-C

Variant names:

• chr4-163472568-A-C
• NM_032136.5:c.1167T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032136.5(TKTL2):​c.1167T>G​(p.Phe389Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 32)
• Consequence: TKTL2 NM_032136.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283

Genes affected

TKTL2 (HGNC:25313): (transketolase like 2) Predicted to enable thiamine pyrophosphate binding activity and transketolase activity. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TKTL2	NM_032136.5	c.1167T>G	p.Phe389Leu	missense_variant	Exon 1 of 1	ENST00000280605.5	NP_115512.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TKTL2	ENST00000280605.5	c.1167T>G	p.Phe389Leu	missense_variant	Exon 1 of 1	6	NM_032136.5	ENSP00000280605.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1167T>G (p.F389L) alteration is located in exon 1 (coding exon 1) of the TKTL2 gene. This alteration results from a T to G substitution at nucleotide position 1167, causing the phenylalanine (F) at amino acid position 389 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	0.92
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.68		Loss of sheet (P = 0.0817);
MVP		0.95
MPC		0.55
ClinPred		0.99	D
GERP RS		-1.1
Varity_R		0.56
gMVP		0.76

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: chr4-164393720;