7-144476230-G-A

Variant names:

• chr7-144476230-G-A
• rs969356
• NM_022445.4:c.614-22567C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022445.4(TPK1):​c.614-22567C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 152,032 control chromosomes in the GnomAD database, including 23,968 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (23968 hom., cov: 33)
• Consequence: TPK1 NM_022445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720
• Publications: 5 publications found

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)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4	c.614-22567C>T		intron_variant	Intron 8 of 8	ENST00000360057.7	NP_071890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPK1	ENST00000360057.7	c.614-22567C>T		intron_variant	Intron 8 of 8	1	NM_022445.4	ENSP00000353165.3

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83637 AN: 151914 Hom.: 23968 Cov.: 33

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.550 AC: 83657 AN: 152032 Hom.: 23968 Cov.: 33 AF XY: 0.538 AC XY: 39989 AN XY: 74312

African (AFR) AF: 0.519 AC: 21520 AN: 41454

American (AMR) AF: 0.461 AC: 7036 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2230 AN: 3468

East Asian (EAS) AF: 0.151 AC: 783 AN: 5176

South Asian (SAS) AF: 0.340 AC: 1635 AN: 4810

European-Finnish (FIN) AF: 0.527 AC: 5562 AN: 10558

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.632 AC: 42958 AN: 67972

Other (OTH) AF: 0.558 AC: 1180 AN: 2114

Alfa AF: 0.605 Hom.: 89677

Bravo AF: 0.546

Asia WGS AF: 0.266 AC: 928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.94
DANN	Benign	0.67
PhyloP100		-0.072
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs969356; hg19: chr7-144173323;