17-29478277-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_020791.4(TAOK1):c.379G>A(p.Glu127Lys) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAOK1 NM_020791.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

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 7 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: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAOK1	NM_020791.4	c.379G>A	p.Glu127Lys	missense_variant	6/20	ENST00000261716.8
TAOK1	NM_025142.1	c.379G>A	p.Glu127Lys	missense_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAOK1	ENST00000261716.8	c.379G>A	p.Glu127Lys	missense_variant	6/20	1	NM_020791.4	P1
TAOK1	ENST00000536202.1	c.379G>A	p.Glu127Lys	missense_variant	6/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental delay with or without intellectual impairment or behavioral abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MVZ Medizinische Genetik Mainz

Nov 15, 2022

ACMG Criteria: PM6, PM2_SUP, PP2, PP3 (ACMG Version 4) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.73	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.71		Gain of methylation at E127 (P = 0.0248);Gain of methylation at E127 (P = 0.0248);
MVP		0.84
MPC		2.2
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-27805295;