chr7-144682946-T-G

Variant names:

• chr7-144682946-T-G
• rs387906935
• NM_022445.4:c.148A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_022445.4(TPK1):​c.148A>C​(p.Asn50His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPK1 NM_022445.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.04
• Publications: 4 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: Likely_pathogenic. The variant received 9 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 7-144682946-T-G is Pathogenic according to our data. Variant chr7-144682946-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 30568.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPK1	NM_022445.4	c.148A>C	p.Asn50His	missense_variant	Exon 4 of 9	ENST00000360057.7	NP_071890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPK1	ENST00000360057.7	c.148A>C	p.Asn50His	missense_variant	Exon 4 of 9	1	NM_022445.4	ENSP00000353165.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Pathogenic:1

Dec 09, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.2	M;.;.
PhyloP100		4.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.028	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.93		Gain of disorder (P = 0.0849);Gain of disorder (P = 0.0849);Gain of disorder (P = 0.0849);
MVP		0.84
MPC		0.67
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.85
Mutation Taster		=16/84	disease causing (ClinVar)

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: rs387906935; hg19: chr7-144380039;