dbSNP rs1432218739: 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53RK	NM_033550.4 link	c.242C>T	p.Thr81Met	missense_variant	Exon 1 of 2	ENST00000372114.4	NP_291028.3
TP53RK-DT	NR_186399.1 link	n.-126G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53RK	ENST00000372114.4 link	c.242C>T	p.Thr81Met	missense_variant	Exon 1 of 2	1	NM_033550.4	ENSP00000361186.3
TP53RK	ENST00000372102.3 link	c.242C>T	p.Thr81Met	missense_variant	Exon 1 of 2	1		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 v4.3

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

T;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

6.9

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.1

N;D

REVEL

Benign

0.20

Sift

Benign

0.23

T;T

Sift4G

Benign

0.28

T;T

Vest4

0.20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over