Genetic Variant TPK1:p.Gly223Gly (chr7-144453608-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_022445.4(TPK1):c.669G>A(p.Gly223Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G223G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TPK1
NM_022445.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.65

Publications

0 publications found

Variant links:

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

TPK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=-0.36).

BP6

Variant 7-144453608-C-T is Benign according to our data. Variant chr7-144453608-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1080578.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.65 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPK1	NM_022445.4	MANE Select	c.669G>A	p.Gly223Gly	synonymous	Exon 9 of 9	NP_071890.2
TPK1	NM_001350879.1		c.669G>A	p.Gly223Gly	synonymous	Exon 9 of 9	NP_001337808.1	Q9H3S4-1
TPK1	NM_001350882.1		c.654G>A	p.Gly218Gly	synonymous	Exon 10 of 10	NP_001337811.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPK1	ENST00000360057.7	TSL:1 MANE Select	c.669G>A	p.Gly223Gly	synonymous	Exon 9 of 9	ENSP00000353165.3	Q9H3S4-1
TPK1	ENST00000378098.8	TSL:1	n.*425G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000367338.4	F8WCM7
TPK1	ENST00000482940.5	TSL:1	n.*700G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000449909.1	F8VVJ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251406

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33462

American (AMR)

AF:

0.000134

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111822

Other (OTH)

AF:

0.0000662

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

2.8

(source)

DANN

Benign

0.79

PhyloP100

-1.7

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over