Genetic Variant TPRKB:c.*129dupA (chr2-73729813-C-CT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000939338.1(TPRKB):c.*129dupA variant causes a splice region change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 0)

Exomes 𝑓: 0.017 ( 1 hom. )

Consequence

TPRKB
ENST00000939338.1 splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00700

Publications

0 publications found

Variant links:

Genes affected

TPRKB (HGNC:24259): (TP53RK binding protein) Enables protein kinase binding activity. Involved in tRNA threonylcarbamoyladenosine modification. Located in cytosol and nucleus. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 5. [provided by Alliance of Genome Resources, Apr 2022]

TPRKB Gene-Disease associations (from GenCC):

Galloway-Mowat syndrome 5
Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
Galloway-Mowat syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TPRKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (1875/140600) while in subpopulation AFR AF = 0.0448 (1695/37868). AF 95% confidence interval is 0.043. There are 35 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000939338.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPRKB	NM_016058.5	MANE Select	c.129_130insA	downstream_gene	N/A	NP_057142.1	Q9Y3C4-1
TPRKB	NM_001330386.2		c.129_130insA	downstream_gene	N/A	NP_001317315.1	Q9Y3C4-3
TPRKB	NM_001330387.2		c.129_130insA	downstream_gene	N/A	NP_001317316.1	Q9Y3C4-3

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
TPRKB	ENST00000939338.1	c.*129dupA	splice_region	Exon 7 of 7	ENSP00000609397.1
TPRKB	ENST00000939338.1	c.*129dupA	3_prime_UTR	Exon 7 of 7	ENSP00000609397.1
TPRKB	ENST00000939335.1	c.*129dupA	3_prime_UTR	Exon 6 of 6	ENSP00000609394.1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

1874

AN:

140606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.000295

Gnomad EAS

AF:

0.000405

Gnomad SAS

AF:

0.000899

Gnomad FIN

AF:

0.000397

Gnomad MID

AF:

0.00336

Gnomad NFE

AF:

0.000982

Gnomad OTH

AF:

0.00876

GnomAD4 exome

AF:

0.0170

AC:

13437

AN:

788412

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

6310

AN XY:

374204

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0684

AC:

1088

AN:

15898

American (AMR)

AF:

0.0279

AC:

109

AN:

3908

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

130

AN:

7960

East Asian (EAS)

AF:

0.0169

AC:

211

AN:

12460

South Asian (SAS)

AF:

0.0189

AC:

475

AN:

25132

European-Finnish (FIN)

AF:

0.0133

AC:

141

AN:

10626

Middle Eastern (MID)

AF:

0.0177

AC:

AN:

1860

European-Non Finnish (NFE)

AF:

0.0158

AC:

10753

AN:

681748

Other (OTH)

AF:

0.0172

AC:

497

AN:

28820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

1076

2151

3227

4302

5378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.0133

AC:

1875

AN:

140600

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

851

AN XY:

67668

show subpopulations

African (AFR)

AF:

0.0448

AC:

1695

AN:

37868

American (AMR)

AF:

0.00620

AC:

AN:

14192

Ashkenazi Jewish (ASJ)

AF:

0.000295

AC:

AN:

3386

East Asian (EAS)

AF:

0.000406

AC:

AN:

4922

South Asian (SAS)

AF:

0.000905

AC:

AN:

4420

European-Finnish (FIN)

AF:

0.000397

AC:

AN:

7560

Middle Eastern (MID)

AF:

0.00365

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000983

AC:

AN:

65134

Other (OTH)

AF:

0.00873

AC:

AN:

1948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000158

Hom.:

949

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.0070

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-73729813-CTTTTTT-CTTTTTTT

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