rs77358162

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-144765897-C-A
• chr7-144765897-C-G
• chr7-144765897-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_022445.4(TPK1):​c.98G>T​(p.Arg33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TPK1 NM_022445.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.756
• Publications: 12 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Thiamin pyrophosphokinase 1 (size 242) in uniprot entity TPK1_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_022445.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2954743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4	c.98G>T	p.Arg33Leu	missense_variant	Exon 3 of 9	ENST00000360057.7	NP_071890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPK1	ENST00000360057.7	c.98G>T	p.Arg33Leu	missense_variant	Exon 3 of 9	1	NM_022445.4	ENSP00000353165.3
TPK1	ENST00000378098.8	n.98G>T		non_coding_transcript_exon_variant	Exon 3 of 10	1		ENSP00000367338.4
TPK1	ENST00000378099.7	c.98G>T	p.Arg33Leu	missense_variant	Exon 3 of 8	3		ENSP00000367339.3
TPK1	ENST00000552881.1	c.98G>T	p.Arg33Leu	missense_variant	Exon 3 of 7	4		ENSP00000448655.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459292 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725884

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110732

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74194

African (AFR) AF: 0.0000242 AC: 1 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 9

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.31	T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.53	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.74	N;.;.
PhyloP100		0.76
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.91	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.34	T;T;.
Polyphen		0.27	B;B;.
Vest4		0.46
MutPred		0.68		Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);
MVP		0.80
MPC		0.20
ClinPred		0.29	T
GERP RS		1.1
Varity_R		0.50
gMVP		0.47
Mutation Taster		=89/11	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; COSMIC: COSV63640258;