2-73730673-T-C

Position:

chr2-73730673-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The ENST00000272424.11(TPRKB):c.328A>G(p.Ile110Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000487 in 1,581,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

TPRKB
ENST00000272424.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.235

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 links:

TPRKB (HGNC:):

TPRKB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a chain EKC/KEOPS complex subunit TPRKB (size 174) in uniprot entity TPRKB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in ENST00000272424.11

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013434827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPRKB	NM_016058.5 linkuse as main transcript	c.328A>G	p.Ile110Val	missense_variant	4/5	ENST00000272424.11	NP_057142.1	Q9Y3C4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPRKB	ENST00000272424.11 linkuse as main transcript	c.328A>G	p.Ile110Val	missense_variant	4/5	1	NM_016058.5	ENSP00000272424.5		Q9Y3C4-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000866

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:

0.000956

GnomAD3 exomes

AF:

0.0000694

AC:

AN:

216280

Hom.:

AF XY:

0.0000763

AC XY:

AN XY:

117918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000193

Gnomad ASJ exome

AF:

0.000750

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000195

Gnomad OTH exome

AF:

0.000197

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1429572

Hom.:

Cov.:

AF XY:

0.0000450

AC XY:

AN XY:

710874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000560

Gnomad4 ASJ exome

AF:

0.000862

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000173

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.328A>G (p.I110V) alteration is located in exon 4 (coding exon 3) of the TPRKB gene. This alteration results from a A to G substitution at nucleotide position 328, causing the isoleucine (I) at amino acid position 110 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with TPRKB-related conditions. This variant is present in population databases (rs374540032, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 110 of the TPRKB protein (p.Ile110Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.7

DANN

Benign

0.87

DEOGEN2

Benign

0.068

T;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.67

T;.;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.3

N;.;.

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.22

N;N;N

REVEL

Benign

0.057

Sift

Benign

0.83

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.14

MVP

0.21

MPC

0.026

ClinPred

0.019

GERP RS

-0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over