rs228584

Variant names:

• chr7-144726266-C-T
• rs228584
• NM_022445.4:c.115+39614G>A

Variant summary

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

The NM_022445.4(TPK1):​c.115+39614G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 152,034 control chromosomes in the GnomAD database, including 14,333 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 0.41 (14333 hom., cov: 33)
• Consequence: TPK1 NM_022445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4	c.115+39614G>A		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.115+39614G>A		intron_variant	Intron 3 of 8	1	NM_022445.4	ENSP00000353165.3

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62865 AN: 151916 Hom.: 14335 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.393

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

GnomAD4 genome AF: 0.414 AC: 62883 AN: 152034 Hom.: 14333 Cov.: 33 AF XY: 0.419 AC XY: 31108 AN XY: 74308

African (AFR) AF: 0.212 AC: 8807 AN: 41492

American (AMR) AF: 0.516 AC: 7871 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3468

East Asian (EAS) AF: 0.490 AC: 2534 AN: 5174

South Asian (SAS) AF: 0.497 AC: 2395 AN: 4822

European-Finnish (FIN) AF: 0.477 AC: 5029 AN: 10542

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33190 AN: 67966

Other (OTH) AF: 0.388 AC: 817 AN: 2106

Alfa AF: 0.450 Hom.: 3260

Bravo AF: 0.409

Asia WGS AF: 0.436 AC: 1514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.54
PhyloP100		0.051
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: rs228584; hg19: chr7-144423359;