2-73729813-CTTTTTT-CTTTT

Variant names:

• chr2-73729813-CTT-C
• rs67805162
• ENST00000939338.1:c.*128_*129delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000939338.1(TPRKB):​c.*128_*129delAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 895,906 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: TPRKB ENST00000939338.1 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.129) population. However there is too low homozygotes in high coverage region: (expected more than 1646, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000939338.1. 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.*128_*129delAA		downstream_gene	N/A	NP_057142.1	Q9Y3C4-1
	TPRKB	NM_001330386.2		c.*128_*129delAA		downstream_gene	N/A	NP_001317315.1	Q9Y3C4-3
	TPRKB	NM_001330387.2		c.*128_*129delAA		downstream_gene	N/A	NP_001317316.1	Q9Y3C4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRKB	ENST00000939338.1		c.*128_*129delAA		splice_region	Exon 7 of 7	ENSP00000609397.1
	TPRKB	ENST00000939338.1		c.*128_*129delAA		3_prime_UTR	Exon 7 of 7	ENSP00000609397.1
	TPRKB	ENST00000939335.1		c.*128_*129delAA		3_prime_UTR	Exon 6 of 6	ENSP00000609394.1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 186 AN: 140568 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000635

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.000810

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00689

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00103

GnomAD4 exome AF: 0.101 AC: 76612 AN: 755344 Hom.: 0 AF XY: 0.102 AC XY: 36512 AN XY: 358512

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0589 AC: 918 AN: 15578

American (AMR) AF: 0.110 AC: 422 AN: 3842

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 934 AN: 7684

East Asian (EAS) AF: 0.135 AC: 1641 AN: 12166

South Asian (SAS) AF: 0.122 AC: 2980 AN: 24366

European-Finnish (FIN) AF: 0.130 AC: 1363 AN: 10492

Middle Eastern (MID) AF: 0.111 AC: 201 AN: 1808

European-Non Finnish (NFE) AF: 0.0998 AC: 65060 AN: 651642

Other (OTH) AF: 0.111 AC: 3093 AN: 27766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00136 AC: 191 AN: 140562 Hom.: 0 Cov.: 0 AF XY: 0.00169 AC XY: 114 AN XY: 67646

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000502 AC: 19 AN: 37874

American (AMR) AF: 0.000634 AC: 9 AN: 14192

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3384

East Asian (EAS) AF: 0.000813 AC: 4 AN: 4922

South Asian (SAS) AF: 0.00 AC: 0 AN: 4422

European-Finnish (FIN) AF: 0.00689 AC: 52 AN: 7552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00155 AC: 101 AN: 65100

Other (OTH) AF: 0.00103 AC: 2 AN: 1946

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 949

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12

Splicing

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

Other links and lift over

dbSNP: rs67805162; hg19: chr2-73956940;