7-144765897-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_022445.4(TPK1):c.98G>A(p.Arg33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 1,611,206 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 67 hom. )

Consequence

TPK1
NM_022445.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.756

Variant links:

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]

TPK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Thiamin pyrophosphokinase 1 (size 242) in uniprot entity TPK1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_022445.4

BP4

Computational evidence support a benign effect (MetaRNN=0.007378876).

BP6

Variant 7-144765897-C-T is Benign according to our data. Variant chr7-144765897-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00517 (786/152048) while in subpopulation NFE AF= 0.00821 (558/67978). AF 95% confidence interval is 0.00765. There are 6 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 9	ENST00000360057.7	NP_071890.2	Q9H3S4-1A0A090N8Y0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPK1	ENST00000360057.7 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 9	1	NM_022445.4	ENSP00000353165.3	Q9H3S4-1
TPK1	ENST00000378098.8 link	n.98G>A		non_coding_transcript_exon_variant	Exon 3 of 10	1		ENSP00000367338.4	F8WCM7
TPK1	ENST00000378099.7 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 8	3		ENSP00000367339.3	F5GZG6
TPK1	ENST00000552881.1 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 7	4		ENSP00000448655.1	F8VRJ6

Frequencies

GnomAD3 genomes

AF:

0.00517

AC:

786

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00692

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00821

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00512

AC:

1272

AN:

248596

Hom.:

AF XY:

0.00501

AC XY:

673

AN XY:

134340

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00823

Gnomad NFE exome

AF:

0.00711

Gnomad OTH exome

AF:

0.00594

GnomAD4 exome

AF:

0.00794

AC:

11589

AN:

1459158

Hom.:

Cov.:

AF XY:

0.00767

AC XY:

5570

AN XY:

725832

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.0171

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000700

Gnomad4 FIN exome

AF:

0.00890

Gnomad4 NFE exome

AF:

0.00898

Gnomad4 OTH exome

AF:

0.00901

GnomAD4 genome

AF:

0.00517

AC:

786

AN:

152048

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

365

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00692

Gnomad4 NFE

AF:

0.00821

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00712

Hom.:

Bravo

AF:

0.00461

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00861

AC:

ExAC

AF:

0.00505

AC:

613

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.00787

EpiControl

AF:

0.00607

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPK1: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Benign:3

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 18, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases

Benign:1

Sep 19, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TPK1-related disorder

Benign:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.31

T;.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.015

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.20

N;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.37

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.17

T;T;.

Polyphen

0.0050

B;B;.

Vest4

0.25

MVP

0.70

MPC

0.19

ClinPred

0.019

GERP RS

1.1

Varity_R

0.24

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over