7-144453615-T-C

Variant names:

• chr7-144453615-T-C
• rs750322523
• NM_022445.4:c.662A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_022445.4(TPK1):​c.662A>G​(p.Tyr221Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,644 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TPK1 NM_022445.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19

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 Likely_pathogenic. Variant got 6 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4	c.662A>G	p.Tyr221Cys	missense_variant	Exon 9 of 9	ENST00000360057.7	NP_071890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPK1	ENST00000360057.7	c.662A>G	p.Tyr221Cys	missense_variant	Exon 9 of 9	1	NM_022445.4	ENSP00000353165.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251400 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.0000109 AC: 16 AN: 1461644 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Uncertain:1

Mar 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine with cysteine at codon 221 of the TPK1 protein (p.Tyr221Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs750322523, ExAC 0.001%). This variant has not been reported in the literature in individuals with TPK1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	2.9	M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.81
MVP		0.87
MPC		0.73
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.78

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: rs750322523; hg19: chr7-144150708;