rs2054442370

Variant names:

• chr7-144453609-C-CCGT
• rs2054442370
• NM_022445.4:c.665_667dupACG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_022445.4(TPK1):​c.665_667dupACG​(p.Asp222dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G223G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPK1 NM_022445.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79
• 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 5 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, 7 uncertain in NM_022445.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_022445.4. Strenght limited to Supporting due to length of the change: 1aa.

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.665_667dupACG	p.Asp222dup	conservative_inframe_insertion	Exon 9 of 9	NP_071890.2
	TPK1	NM_001350879.1		c.665_667dupACG	p.Asp222dup	conservative_inframe_insertion	Exon 9 of 9	NP_001337808.1	Q9H3S4-1
	TPK1	NM_001350882.1		c.650_652dupACG	p.Asp217dup	conservative_inframe_insertion	Exon 10 of 10	NP_001337811.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPK1	ENST00000360057.7	TSL:1 MANE Select	c.665_667dupACG	p.Asp222dup	conservative_inframe_insertion	Exon 9 of 9	ENSP00000353165.3	Q9H3S4-1
	TPK1	ENST00000378098.8	TSL:1	n.*421_*423dupACG		non_coding_transcript_exon	Exon 10 of 10	ENSP00000367338.4	F8WCM7
	TPK1	ENST00000482940.5	TSL:1	n.*696_*698dupACG		non_coding_transcript_exon	Exon 12 of 12	ENSP00000449909.1	F8VVJ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

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

Other links and lift over

dbSNP: rs2054442370; hg19: chr7-144150702;