chr20-46689173-G-A

Position:

• chr20-46689173-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

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 Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TP53RK NM_033550.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.92

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 5 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-46689173-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.29660708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53RK	NM_033550.4	c.242C>T	p.Thr81Met	missense_variant	1/2	ENST00000372114.4	NP_291028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53RK	ENST00000372114.4	c.242C>T	p.Thr81Met	missense_variant	1/2	1	NM_033550.4	ENSP00000361186.3
TP53RK	ENST00000372102.3	c.242C>T	p.Thr81Met	missense_variant	1/2	1		ENSP00000361174.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000956 AC: 13 AN: 1360176 Hom.: 0 Cov.: 31 AF XY: 0.0000105 AC XY: 7 AN XY: 669462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000303

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000204 Hom.: 0

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	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.011	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N;D
REVEL	Benign	0.20
Sift	Benign	0.23	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.76	P;P
Vest4		0.20
MVP		0.22
MPC		0.69
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.27

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1432218739; hg19: chr20-45317812;