7-144682942-CG-GA

Variant names:

• chr7-144682942-CG-GA
• NM_022445.4:c.151_152delCGinsTC
• TPK1 p.Arg51Ser

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_022445.4(TPK1):​c.151_152delCGinsTC​(p.Arg51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R51H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TPK1 NM_022445.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52
• Publications: 0 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), PanelApp Australia
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_022445.4

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.151_152delCGinsTC	p.Arg51Ser	missense	N/A	NP_071890.2
	TPK1	NM_001350879.1		c.151_152delCGinsTC	p.Arg51Ser	missense	N/A	NP_001337808.1	Q9H3S4-1
	TPK1	NM_001350881.1		c.151_152delCGinsTC	p.Arg51Ser	missense	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.151_152delCGinsTC	p.Arg51Ser	missense	N/A	ENSP00000353165.3	Q9H3S4-1
	TPK1	ENST00000378098.8	TSL:1	n.151_152delCGinsTC		non_coding_transcript_exon	Exon 4 of 10	ENSP00000367338.4	F8WCM7
	TPK1	ENST00000481645.5	TSL:1	n.241_242delCGinsTC		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-144380035;