7-144453621-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_022445.4(TPK1):c.656A>G(p.Asn219Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N219N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TPK1 NM_022445.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.26

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 Likely_pathogenic. Variant got 9 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 7-144453621-T-C is Pathogenic according to our data. Variant chr7-144453621-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30572.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPK1	NM_022445.4	c.656A>G	p.Asn219Ser	missense_variant	9/9	ENST00000360057.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPK1	ENST00000360057.7	c.656A>G	p.Asn219Ser	missense_variant	9/9	1	NM_022445.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251414 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461624 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000585 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 02, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM2,PM3,PP2,PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 09, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 16, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPK1 function (PMID: 30483896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPK1 protein function. ClinVar contains an entry for this variant (Variation ID: 30572). This missense change has been observed in individual(s) with thiamine metabolism dysfunction syndrome (PMID: 22152682, 28747443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs371271054, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 219 of the TPK1 protein (p.Asn219Ser). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2015

The N219S missense variant in the TPK1 gene has been reported previously in association with thiaminepyrophosphokinase deficiency in a patient who was compound heterozygous for N219S and a frameshiftvariant (Mayr et al. 2011). N219S occurs at a position that is conserved across species, in silico analysispredicts that N219S is probably damaging to the protein structure/function, and a missense variant in anearby residue (D222H) has also been reported in the Human Gene Mutation Database in association withthiamine pyrophosphokinase deficiency (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we interpret N219S to be a pathogenic variant. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.656A>G (p.N219S) alteration is located in exon 9 (coding exon 8) of the TPK1 gene. This alteration results from a A to G substitution at nucleotide position 656, causing the asparagine (N) at amino acid position 219 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.91
MVP		0.88
MPC		0.59
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.91

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: rs371271054; hg19: chr7-144150714;