chr7-144722784-G-A

Variant names:

• chr7-144722784-G-A
• rs228582
• NM_022445.4:c.116-39806C>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.116-39806C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 151,544 control chromosomes in the GnomAD database, including 31,228 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 0.63 (31228 hom., cov: 27)
• Consequence: TPK1 NM_022445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 8 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 (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4	c.116-39806C>T		intron_variant	Intron 3 of 8	ENST00000360057.7	NP_071890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPK1	ENST00000360057.7	c.116-39806C>T		intron_variant	Intron 3 of 8	1	NM_022445.4	ENSP00000353165.3

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95098 AN: 151426 Hom.: 31183 Cov.: 27

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.628 AC: 95203 AN: 151544 Hom.: 31228 Cov.: 27 AF XY: 0.627 AC XY: 46389 AN XY: 73986

African (AFR) AF: 0.833 AC: 34429 AN: 41330

American (AMR) AF: 0.623 AC: 9491 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1909 AN: 3462

East Asian (EAS) AF: 0.492 AC: 2510 AN: 5102

South Asian (SAS) AF: 0.529 AC: 2529 AN: 4782

European-Finnish (FIN) AF: 0.551 AC: 5763 AN: 10456

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36454 AN: 67868

Other (OTH) AF: 0.577 AC: 1211 AN: 2098

Alfa AF: 0.559 Hom.: 43188

Bravo AF: 0.645

Asia WGS AF: 0.499 AC: 1736 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	0.82
DANN	Benign	0.25
PhyloP100		0.10
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: rs228582; hg19: chr7-144419877;