17-29478347-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_020791.4(TAOK1):c.449G>T(p.Arg150Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TAOK1 NM_020791.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.98

Genes affected

TAOK1 (HGNC:29259): (TAO kinase 1) Enables alpha-tubulin binding activity; beta-tubulin binding activity; and kinase activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; negative regulation of microtubule depolymerization; and positive regulation of JNK cascade. Located in microtubule cytoskeleton and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 253) in uniprot entity TAOK1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_020791.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TAOK1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-29478347-G-T is Pathogenic according to our data. Variant chr17-29478347-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985562.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAOK1	NM_020791.4	c.449G>T	p.Arg150Ile	missense_variant, splice_region_variant	6/20	ENST00000261716.8
TAOK1	NM_025142.1	c.449G>T	p.Arg150Ile	missense_variant, splice_region_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAOK1	ENST00000261716.8	c.449G>T	p.Arg150Ile	missense_variant, splice_region_variant	6/20	1	NM_020791.4	P1
TAOK1	ENST00000536202.1	c.449G>T	p.Arg150Ile	missense_variant, splice_region_variant	6/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1409948 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 699930

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.449G>T (p.R150I) alteration is located in exon 6 (coding exon 5) of the TAOK1 gene. This alteration results from a G to T substitution at nucleotide position 449. This change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration causes the arginine (R) at amino acid position 150 to be replaced by an isoleucine (I). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the TAOK1 c.449G>T alteration was not observed, with coverage at this position. The altered nucleotide is conserved throughout evolution:_x000D_ _x000D_ The c.449G nucleotide is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.R150 amino acid is located in the conserved kinase domain, also known as catalytic domain, of the TAOK1 protein. The catalytic domains of protein kinases contain 12 conserved subdomains that fold into a common catalytic core structure. R150 is part of the catalytic loop of subdomain VIB and adjacent to residue D151, which is likely important for the catalytic activity of that region (Hanks, 1995). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.R150I amino acid change is predicted to be deleterious by in silico analysis. Additionally, this nucleotide change is predicted to weaken the native splice donor site based on the BDGP and ESEfinder splice site in silico tools; however, direct evidence is unavailable. Based on the available evidence, this alteration is classified as likely pathogenic. -

DEVELOPMENTAL DELAY WITHOUT INTELLECTUAL IMPAIRMENT OR BEHAVIORAL ABNORMALITIES Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	35
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.92		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.92
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.86
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2030989355; hg19: chr17-27805365;