Genetic Variant TPK1:c.258+288G>C (chr7-144648519-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022445.4(TPK1):c.258+288G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 755,600 control chromosomes in the GnomAD database, including 809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 453 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 356 hom. )

Consequence

TPK1
NM_022445.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.247

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 links:

EEF1A1P10 (HGNC:3205): (eukaryotic translation elongation factor 1 alpha 1 pseudogene 10)

EEF1A1P10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 7-144648519-C-G is Benign according to our data. Variant chr7-144648519-C-G is described in ClinVar as Benign. ClinVar VariationId is 1248149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
TPK1	NM_022445.4	MANE Select	c.258+288G>C	intron	N/A	NP_071890.2
TPK1	NM_001350879.1		c.258+288G>C	intron	N/A	NP_001337808.1	Q9H3S4-1
TPK1	NM_001350881.1		c.258+288G>C	intron	N/A	NP_001337810.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPK1	ENST00000360057.7	TSL:1 MANE Select	c.258+288G>C	intron	N/A	ENSP00000353165.3	Q9H3S4-1
TPK1	ENST00000378098.8	TSL:1	n.258+288G>C	intron	N/A	ENSP00000367338.4	F8WCM7
TPK1	ENST00000481645.5	TSL:1	n.348+288G>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0400

AC:

6076

AN:

152080

Hom.:

446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.0382

GnomAD4 exome

AF:

0.00674

AC:

4066

AN:

603402

Hom.:

356

Cov.:

AF XY:

0.00529

AC XY:

1744

AN XY:

329816

show subpopulations

African (AFR)

AF:

0.166

AC:

3032

AN:

18226

American (AMR)

AF:

0.00883

AC:

378

AN:

42822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20216

East Asian (EAS)

AF:

0.00

AC:

AN:

34498

South Asian (SAS)

AF:

0.000330

AC:

AN:

69688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36602

Middle Eastern (MID)

AF:

0.00980

AC:

AN:

3774

European-Non Finnish (NFE)

AF:

0.000515

AC:

178

AN:

345834

Other (OTH)

AF:

0.0132

AC:

418

AN:

31742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.590

Heterozygous variant carriers

154

307

461

614

768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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

AF:

0.0401

AC:

6103

AN:

152198

Hom.:

453

Cov.:

AF XY:

0.0392

AC XY:

2916

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.140

AC:

5793

AN:

41482

American (AMR)

AF:

0.0122

AC:

187

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68012

Other (OTH)

AF:

0.0378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

272

544

815

1087

1359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0315

Hom.:

Bravo

AF:

0.0458

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.88

(source)

DANN

Benign

0.58

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over