rs2054437657

Variant names:

• chr7-144453590-C-T
• rs2054437657
• NM_022445.4:c.687G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_022445.4(TPK1):​c.687G>A​(p.Val229Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPK1 NM_022445.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 7-144453590-C-T is Benign according to our data. Variant chr7-144453590-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 855208.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.051 with no splicing effect.

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.687G>A	p.Val229Val	synonymous	Exon 9 of 9	NP_071890.2
	TPK1	NM_001350879.1		c.687G>A	p.Val229Val	synonymous	Exon 9 of 9	NP_001337808.1	Q9H3S4-1
	TPK1	NM_001350882.1		c.672G>A	p.Val224Val	synonymous	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.687G>A	p.Val229Val	synonymous	Exon 9 of 9	ENSP00000353165.3	Q9H3S4-1
	TPK1	ENST00000378098.8	TSL:1	n.*443G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000367338.4	F8WCM7
	TPK1	ENST00000482940.5	TSL:1	n.*718G>A		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: Likely benign

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
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		-0.051

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: rs2054437657; hg19: chr7-144150683; COSMIC: COSV105273825; COSMIC: COSV105273825;