rs781905246

Positions:

• chr3-53231529-C-CCAGAAGATAAGGAGGTAG
• chr3-53231529-C-CNNNNNNNNNNNNNNNNNN

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_001064.4(TKT):​c.769_770insCTACCTCCTTATCTTCTG​(p.Trp257delinsSerThrSerLeuSerSerGly) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: TKT NM_001064.4 conservative_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.31

Genes affected

TKT (HGNC:11834): (transketolase) This gene encodes a thiamine-dependent enzyme which plays a role in the channeling of excess sugar phosphates to glycolysis in the pentose phosphate pathway. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2012]

TKT (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001064.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-53231529-C-CCAGAAGATAAGGAGGTAG is Pathogenic according to our data. Variant chr3-53231529-C-CCAGAAGATAAGGAGGTAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TKT	NM_001064.4	c.769_770insCTACCTCCTTATCTTCTG	p.Trp257delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	7/14	ENST00000462138.6	NP_001055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TKT	ENST00000462138.6	c.769_770insCTACCTCCTTATCTTCTG	p.Trp257delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	7/14	1	NM_001064.4	ENSP00000417773.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

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: 0.000119 AC: 30 AN: 251154 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00299

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: 0.0000705 AC: 103 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52 AN XY: 727152

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

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

Alfa AF: 0.000574 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transketolase deficiency Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 20, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 19, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2024	Published functional studies demonstrate a damaging effect with no residual transketolase enzyme activity (PMID: 27259054); In-frame deletion of 1 amino acid and insertion of 7 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27259054, 32828637, 36978159) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 30, 2021	This variant, c.769_770insCTACCTCCTTATCTTCTG, is a complex sequence change that results in the deletion of 1 and insertion of 7 amino acid(s) in the TKT protein (p.Trp257delinsSerThrSerLeuSerSerGly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with transketolase deficiency (PMID: 27259054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243092). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781905246; hg19: chr3-53265545;