20-46689173-G-C

Variant names:

• chr20-46689173-G-C
• rs1432218739
• NM_033550.4:c.242C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_033550.4(TP53RK):​c.242C>G​(p.Thr81Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T81T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53RK NM_033550.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.92
• Publications: 4 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 20-46689173-G-C is Pathogenic according to our data. 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.

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>G	p.Thr81Arg	missense	Exon 1 of 2	NP_291028.3
	TP53RK-DT	NR_186399.1		n.-126G>C		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>G	p.Thr81Arg	missense	Exon 1 of 2	ENSP00000361186.3
	TP53RK	ENST00000372102.3	TSL:1	c.242C>G	p.Thr81Arg	missense	Exon 1 of 2	ENSP00000361174.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Galloway-Mowat syndrome 4 Pathogenic:1

Oct 27, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.31
Sift	Benign	0.046	D
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.73		Loss of phosphorylation at T81 (P = 0.0103)
MVP		0.40
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1432218739; hg19: chr20-45317812;