chr7-144765897-C-G

Variant names:

• chr7-144765897-C-G
• rs77358162
• NM_022445.4:c.98G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022445.4(TPK1):​c.98G>C​(p.Arg33Pro) variant causes a missense 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPK1 NM_022445.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35468078).

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.98G>C	p.Arg33Pro	missense	Exon 3 of 9	NP_071890.2
	TPK1	NM_001350879.1		c.98G>C	p.Arg33Pro	missense	Exon 3 of 9	NP_001337808.1	Q9H3S4-1
	TPK1	NM_001350881.1		c.98G>C	p.Arg33Pro	missense	Exon 3 of 10	NP_001337810.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPK1	ENST00000360057.7	TSL:1 MANE Select	c.98G>C	p.Arg33Pro	missense	Exon 3 of 9	ENSP00000353165.3	Q9H3S4-1
	TPK1	ENST00000378098.8	TSL:1	n.98G>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000367338.4	F8WCM7
	TPK1	ENST00000889991.1		c.98G>C	p.Arg33Pro	missense	Exon 3 of 9	ENSP00000560050.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.49
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.76
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.45
Sift	Benign	0.99	T
Sift4G	Benign	0.40	T
Polyphen		0.013	B
Vest4		0.72
MutPred		0.68		Loss of MoRF binding (P = 0.0129)
MVP		0.74
MPC		0.24
ClinPred		0.45	T
GERP RS		1.1
Varity_R		0.90
gMVP		0.74
Mutation Taster		=64/36	polymorphism

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: rs77358162; hg19: chr7-144462990;