rs10224675

Variant names:

• chr7-144595669-A-G
• rs10224675
• NM_022445.4:c.355-4100T>C

Variant summary

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

The NM_022445.4(TPK1):​c.355-4100T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 151,888 control chromosomes in the GnomAD database, including 143 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 0.023 (143 hom., cov: 31)
• Consequence: TPK1 NM_022445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 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.355-4100T>C		intron	N/A	NP_071890.2
	TPK1	NM_001350879.1		c.355-4100T>C		intron	N/A	NP_001337808.1
	TPK1	NM_001350881.1		c.355-4100T>C		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.355-4100T>C		intron	N/A	ENSP00000353165.3
	TPK1	ENST00000378098.8	TSL:1	n.*111-4100T>C		intron	N/A	ENSP00000367338.4
	TPK1	ENST00000482940.5	TSL:1	n.*280-4100T>C		intron	N/A	ENSP00000449909.1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3542 AN: 151770 Hom.: 143 Cov.: 31

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.0226

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

GnomAD4 genome AF: 0.0234 AC: 3547 AN: 151888 Hom.: 143 Cov.: 31 AF XY: 0.0232 AC XY: 1724 AN XY: 74272

African (AFR) AF: 0.0804 AC: 3330 AN: 41430

American (AMR) AF: 0.00870 AC: 133 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000487 AC: 33 AN: 67824

Other (OTH) AF: 0.0223 AC: 47 AN: 2104

Alfa AF: 0.00648 Hom.: 28

Bravo AF: 0.0267

Asia WGS AF: 0.00347 AC: 12 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.6
DANN	Benign	0.66
PhyloP100		0.37
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: rs10224675; hg19: chr7-144292762;