3-53231529-C-CCAGAAGATAAGGAGGTAG

Variant names:

• chr3-53231529-C-CCAGAAGATAAGGAGGTAG
• rs781905246
• NM_001064.4:c.769_770insCTACCTCCTTATCTTCTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM4 PP3 PP5_Very_Strong

The NM_001258028.2(TKT):​c.793_794insCTACCTCCTTATCTTCTG​(p.Trp265delinsSerThrSerLeuSerSerGly) 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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_001258028.2 conservative_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.31
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• transketolase deficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001258028.2.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 243092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258028.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TKT	NM_001064.4	MANE Select	c.769_770insCTACCTCCTTATCTTCTG	p.Trp257delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	Exon 7 of 14	NP_001055.1
	TKT	NM_001258028.2		c.793_794insCTACCTCCTTATCTTCTG	p.Trp265delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	Exon 8 of 15	NP_001244957.1
	TKT	NM_001135055.3		c.769_770insCTACCTCCTTATCTTCTG	p.Trp257delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	Exon 7 of 15	NP_001128527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TKT	ENST00000462138.6	TSL:1 MANE Select	c.769_770insCTACCTCCTTATCTTCTG	p.Trp257delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	Exon 7 of 14	ENSP00000417773.1
	TKT	ENST00000423525.6	TSL:1	c.769_770insCTACCTCCTTATCTTCTG	p.Trp257delinsSerThrSerLeuSerSerGly	conservative_inframe_insertion	Exon 7 of 15	ENSP00000405455.2
	TKT	ENST00000472528.5	TSL:1	n.*688_*689insCTACCTCCTTATCTTCTG		non_coding_transcript_exon	Exon 9 of 9	ENSP00000417312.1

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

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251154 AF XY: 0.000140

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 79 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111926

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000574 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	Transketolase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs781905246; hg19: chr3-53265545;