Genetic Variant TP53RK:p.Thr81Met (chr20-46689173-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_033550.4(TP53RK):c.242C>T(p.Thr81Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000956 in 1,360,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T81R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TP53RK
NM_033550.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.92

Publications

4 publications found

Variant links:

Genes affected

TP53RK (HGNC:16197): (TP53 regulating kinase) Enables p53 binding activity and protein serine/threonine kinase activity. Involved in protein phosphorylation. Located in cytoplasm and nucleus. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 4. [provided by Alliance of Genome Resources, Apr 2022]

TP53RK links:

TP53RK-DT (HGNC:55243): (TP53RK divergent transcript)

TP53RK-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-46689173-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 444881.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.29660708).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033550.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53RK	NM_033550.4	MANE Select	c.242C>T	p.Thr81Met	missense	Exon 1 of 2	NP_291028.3
	TP53RK-DT	NR_186399.1		n.-126G>A		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53RK	ENST00000372114.4	TSL:1 MANE Select	c.242C>T	p.Thr81Met	missense	Exon 1 of 2	ENSP00000361186.3
	TP53RK	ENST00000372102.3	TSL:1	c.242C>T	p.Thr81Met	missense	Exon 1 of 2	ENSP00000361174.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000181

AC:

AN:

110724

AF XY:

0.0000165

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000480

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000956

AC:

AN:

1360176

Hom.:

Cov.:

AF XY:

0.0000105

AC XY:

AN XY:

669462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29252

American (AMR)

AF:

0.00

AC:

AN:

34028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23946

East Asian (EAS)

AF:

0.00

AC:

AN:

34420

South Asian (SAS)

AF:

0.00

AC:

AN:

75322

European-Finnish (FIN)

AF:

0.0000303

AC:

AN:

33012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

1069352

Other (OTH)

AF:

0.00

AC:

AN:

56822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000204

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.011

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

6.9

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Benign

0.23

Sift4G

Benign

0.28

Polyphen

0.76

Vest4

0.20

MVP

0.22

MPC

0.69

ClinPred

0.88

GERP RS

4.6

PromoterAI

0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.27

Mutation Taster

=52/48

polymorphism

(source)

Splicing

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