Genetic Variant TPK1:p.Arg33His (chr7-144765897-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33C) has been classified as Uncertain significance.

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

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

childhood encephalopathy due to thiamine pyrophosphokinase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

TPK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPK1	NM_022445.4	MANE Select	c.98G>A	p.Arg33His	missense	Exon 3 of 9	NP_071890.2
TPK1	NM_001350879.1		c.98G>A	p.Arg33His	missense	Exon 3 of 9	NP_001337808.1	Q9H3S4-1
TPK1	NM_001350881.1		c.98G>A	p.Arg33His	missense	Exon 3 of 10	NP_001337810.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPK1	ENST00000360057.7	TSL:1 MANE Select	c.98G>A	p.Arg33His	missense	Exon 3 of 9	ENSP00000353165.3	Q9H3S4-1
TPK1	ENST00000378098.8	TSL:1	n.98G>A		non_coding_transcript_exon	Exon 3 of 10	ENSP00000367338.4	F8WCM7
TPK1	ENST00000889991.1		c.98G>A	p.Arg33His	missense	Exon 3 of 9	ENSP00000560050.1

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

GnomAD2 exomes

AF:

0.00512

AC:

1272

AN:

248596

AF XY:

0.00501

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 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

African (AFR)

AF:

0.00159

AC:

AN:

33376

American (AMR)

AF:

0.00211

AC:

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

446

AN:

26044

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39510

South Asian (SAS)

AF:

0.0000700

AC:

AN:

85746

European-Finnish (FIN)

AF:

0.00890

AC:

475

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00898

AC:

9971

AN:

1110614

Other (OTH)

AF:

0.00901

AC:

543

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

533

1067

1600

2134

2667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

380

760

1140

1520

1900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00517

AC:

786

AN:

152048

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

365

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41486

American (AMR)

AF:

0.00111

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00692

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00821

AC:

558

AN:

67978

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00670

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (3)

Inborn genetic diseases (1)

not specified (1)

TPK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.31

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.015

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.20

PhyloP100

0.76

PrimateAI

Benign

0.32

PROVEAN

Benign

0.37

REVEL

Benign

0.14

Sift

Benign

0.30

Sift4G

Benign

0.17

Polyphen

0.0050

Vest4

0.25

MVP

0.70

MPC

0.19

ClinPred

0.019

GERP RS

1.1

Varity_R

0.24

gMVP

0.32

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over