Genetic Variant TPRKB:c.*125_*129delAAAAA (chr2-73729813-CTTTTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000939338.1(TPRKB):c.*125_*129delAAAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 794,410 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPRKB
ENST00000939338.1 splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.16

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.125_129delAAAAA	downstream_gene	N/A	NP_057142.1	Q9Y3C4-1
TPRKB	NM_001330386.2		c.125_129delAAAAA	downstream_gene	N/A	NP_001317315.1	Q9Y3C4-3
TPRKB	NM_001330387.2		c.125_129delAAAAA	downstream_gene	N/A	NP_001317316.1	Q9Y3C4-3

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
TPRKB	ENST00000939338.1	c.125_129delAAAAA	splice_region	Exon 7 of 7	ENSP00000609397.1
TPRKB	ENST00000939338.1	c.125_129delAAAAA	3_prime_UTR	Exon 7 of 7	ENSP00000609397.1
TPRKB	ENST00000939335.1	c.125_129delAAAAA	3_prime_UTR	Exon 6 of 6	ENSP00000609394.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

140628

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00000755

AC:

AN:

794410

Hom.:

AF XY:

0.0000106

AC XY:

AN XY:

377038

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

16128

American (AMR)

AF:

0.00

AC:

AN:

3922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8008

East Asian (EAS)

AF:

0.00

AC:

AN:

12524

South Asian (SAS)

AF:

0.00

AC:

AN:

25270

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

10688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1874

European-Non Finnish (NFE)

AF:

0.00000582

AC:

AN:

686932

Other (OTH)

AF:

0.0000344

AC:

AN:

29064

⚠️ 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: 0.225

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

140628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67660

African (AFR)

AF:

0.00

AC:

AN:

37822

American (AMR)

AF:

0.00

AC:

AN:

14184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4938

South Asian (SAS)

AF:

0.00

AC:

AN:

4450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65150

Other (OTH)

AF:

0.00

AC:

AN:

1942

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Splicing

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

Publications

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2-73729813-CTTTTTT-CT

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