7-144714388-C-T

Variant names:

• chr7-144714388-C-T
• rs228581
• NM_022445.4:c.116-31410G>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.116-31410G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 151,864 control chromosomes in the GnomAD database, including 6,976 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 0.27 (6976 hom., cov: 32)
• Consequence: TPK1 NM_022445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.347
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPK1	NM_022445.4	MANE Select	c.116-31410G>A		intron	N/A	NP_071890.2
	TPK1	NM_001350879.1		c.116-31410G>A		intron	N/A	NP_001337808.1
	TPK1	NM_001350881.1		c.116-31410G>A		intron	N/A	NP_001337810.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPK1	ENST00000360057.7	TSL:1 MANE Select	c.116-31410G>A		intron	N/A	ENSP00000353165.3
	TPK1	ENST00000378098.8	TSL:1	n.116-31410G>A		intron	N/A	ENSP00000367338.4
	TPK1	ENST00000481645.5	TSL:1	n.205+24885G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41468 AN: 151746 Hom.: 6977 Cov.: 32

Gnomad AFR AF: 0.0721

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.273 AC: 41470 AN: 151864 Hom.: 6976 Cov.: 32 AF XY: 0.279 AC XY: 20736 AN XY: 74228

African (AFR) AF: 0.0719 AC: 2982 AN: 41448

American (AMR) AF: 0.380 AC: 5797 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3468

East Asian (EAS) AF: 0.455 AC: 2353 AN: 5174

South Asian (SAS) AF: 0.395 AC: 1895 AN: 4798

European-Finnish (FIN) AF: 0.345 AC: 3624 AN: 10500

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.336 AC: 22833 AN: 67908

Other (OTH) AF: 0.259 AC: 546 AN: 2110

Alfa AF: 0.302 Hom.: 5273

Bravo AF: 0.268

Asia WGS AF: 0.316 AC: 1093 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.3
DANN	Benign	0.69
PhyloP100		-0.35
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: rs228581; hg19: chr7-144411481;