rs113536847

chr7-144453614-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_022445.4(TPK1):c.663C>T(p.Tyr221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,876 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (9 hom.)
• Consequence: TPK1 NM_022445.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.19

Genes affected

TPK1 (HGNC:17358): (thiamin pyrophosphokinase 1) The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine to thiamine pyrophosphate, a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-144453614-G-A is Benign according to our data. Variant chr7-144453614-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00239 (364/152266) while in subpopulation SAS AF= 0.00395 (19/4814). AF 95% confidence interval is 0.00351. There are 0 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPK1	NM_022445.4	c.663C>T	p.Tyr221=	synonymous_variant	9/9	ENST00000360057.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPK1	ENST00000360057.7	c.663C>T	p.Tyr221=	synonymous_variant	9/9	1	NM_022445.4	P1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00253 AC: 636 AN: 251394 Hom.: 1 AF XY: 0.00291 AC XY: 396 AN XY: 135862

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00425

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00336 AC: 4913 AN: 1461610 Hom.: 9 Cov.: 30 AF XY: 0.00339 AC XY: 2465 AN XY: 727124

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00493

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74444

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00320 Hom.: 0

Bravo AF: 0.00221

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

TPK1: BP4, BP7 -

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.0
Dann	Benign	0.85

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: rs113536847; hg19: chr7-144150707; COSMIC: COSV63641482; COSMIC: COSV63641482;