7-144765897-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.756

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 -18 ACMG points.

• PM1: In a chain Thiamin pyrophosphokinase 1 (size 242) in uniprot entity TPK1_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) 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 GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPK1	NM_022445.4	c.98G>A	p.Arg33His	missense_variant	3/9	ENST00000360057.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPK1	ENST00000360057.7	c.98G>A	p.Arg33His	missense_variant	3/9	1	NM_022445.4	P1
TPK1	ENST00000378098.8	c.98G>A	p.Arg33His	missense_variant, NMD_transcript_variant	3/10	1
TPK1	ENST00000378099.7	c.98G>A	p.Arg33His	missense_variant	3/8	3
TPK1	ENST00000552881.1	c.98G>A	p.Arg33His	missense_variant	3/7	4

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 786 AN: 151930 Hom.: 6 Cov.: 32

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.: 6 AF XY: 0.00501 AC XY: 673 AN XY: 134340

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.: 67 Cov.: 31 AF XY: 0.00767 AC XY: 5570 AN XY: 725832

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.: 6 Cov.: 32 AF XY: 0.00491 AC XY: 365 AN XY: 74322

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.: 8

Bravo AF: 0.00461

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00861 AC: 74

ExAC AF: 0.00505 AC: 613

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00787

EpiControl AF: 0.00607

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TPK1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 13, 2016	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2017	- -

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2014

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

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	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.82
DEOGEN2	Benign	0.31	T;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.40	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.20	N;.;.
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs77358162; hg19: chr7-144462990;