20-46686923-C-T

Variant names:

• chr20-46686923-C-T
• NM_033550.4:c.592G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_033550.4(TP53RK):​c.592G>A​(p.Val198Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53RK NM_033550.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Protein kinase (size 220) in uniprot entity PRPK_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_033550.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53RK	NM_033550.4	c.592G>A	p.Val198Ile	missense_variant	Exon 2 of 2	ENST00000372114.4	NP_291028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53RK	ENST00000372114.4	c.592G>A	p.Val198Ile	missense_variant	Exon 2 of 2	1	NM_033550.4	ENSP00000361186.3
TP53RK	ENST00000372102	c.*231G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000361174.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Galloway-Mowat syndrome 4 Uncertain:1

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.75		Loss of catalytic residue at V198 (P = 0.039);
MVP		0.26
MPC		0.96
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.53

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-45315562;