chr2-73730594-A-G

Position:

• chr2-73730594-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_016058.5(TPRKB):​c.407T>C​(p.Leu136Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L136V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPRKB NM_016058.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 7.15

Genes affected

TPRKB (HGNC:24259): (TP53RK binding protein) Enables protein kinase binding activity. Involved in tRNA threonylcarbamoyladenosine modification. Located in cytosol and nucleus. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 5. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain EKC/KEOPS complex subunit TPRKB (size 174) in uniprot entity TPRKB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_016058.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPRKB	NM_016058.5	c.407T>C	p.Leu136Pro	missense_variant	4/5	ENST00000272424.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPRKB	ENST00000272424.11	c.407T>C	p.Leu136Pro	missense_variant	4/5	1	NM_016058.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Galloway-Mowat syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 27, 2017

- -

Nephrotic syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	T;.;T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.86		Gain of relative solvent accessibility (P = 0.0023);.;.;
MVP		0.85
MPC		0.27
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553433412; hg19: chr2-73957721;