2-73730026-A-T

Variant names:

• chr2-73730026-A-T
• rs754783287
• NM_016058.5:c.445T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_016058.5(TPRKB):​c.445T>A​(p.Tyr149Asn) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y149C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPRKB NM_016058.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.03
• Publications: 0 publications found

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]

TPRKB Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 5

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-73730025-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 444885.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 2-73730026-A-T is Pathogenic according to our data. Variant chr2-73730026-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3065453.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016058.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRKB	NM_016058.5	MANE Select	c.445T>A	p.Tyr149Asn	missense	Exon 5 of 5	NP_057142.1	Q9Y3C4-1
	TPRKB	NM_001330386.2		c.562T>A	p.Tyr188Asn	missense	Exon 6 of 6	NP_001317315.1	Q9Y3C4-3
	TPRKB	NM_001330387.2		c.562T>A	p.Tyr188Asn	missense	Exon 6 of 6	NP_001317316.1	Q9Y3C4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRKB	ENST00000272424.11	TSL:1 MANE Select	c.445T>A	p.Tyr149Asn	missense	Exon 5 of 5	ENSP00000272424.5	Q9Y3C4-1
	TPRKB	ENST00000318190.7	TSL:5	c.562T>A	p.Tyr188Asn	missense	Exon 6 of 6	ENSP00000325398.7	Q9Y3C4-3
	TPRKB	ENST00000409716.6	TSL:5	c.562T>A	p.Tyr188Asn	missense	Exon 6 of 6	ENSP00000386936.2	Q9Y3C4-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408328 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698804

African (AFR) AF: 0.00 AC: 0 AN: 32010

American (AMR) AF: 0.00 AC: 0 AN: 36176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24412

East Asian (EAS) AF: 0.00 AC: 0 AN: 38316

South Asian (SAS) AF: 0.00 AC: 0 AN: 79450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083578

Other (OTH) AF: 0.00 AC: 0 AN: 57888

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Galloway-Mowat syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.074	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.80		Gain of disorder (P = 0.0144)
MVP		0.84
MPC		0.26
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.84
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs754783287; hg19: chr2-73957153;