12-118189826-G-A

Position:

• chr12-118189826-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_016281.4(TAOK3):​c.1310C>T​(p.Thr437Met) 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: TAOK3 NM_016281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57

Genes affected

TAOK3 (HGNC:18133): (TAO kinase 3) The protein encoded by this gene is a serine/threonine protein kinase that activates the p38/MAPK14 stress-activated MAPK cascade but inhibits the basal activity of the MAPK8/JNK cascade. The encoded protein is a member of the GCK subfamily of STE20-like kinases. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TAOK3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAOK3	NM_016281.4	c.1310C>T	p.Thr437Met	missense_variant	14/21	ENST00000392533.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAOK3	ENST00000392533.8	c.1310C>T	p.Thr437Met	missense_variant	14/21	1	NM_016281.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2021

The c.1310C>T (p.T437M) alteration is located in exon 14 (coding exon 12) of the TAOK3 gene. This alteration results from a C to T substitution at nucleotide position 1310, causing the threonine (T) at amino acid position 437 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.30		Loss of phosphorylation at T437 (P = 0.0379);Loss of phosphorylation at T437 (P = 0.0379);
MVP		0.72
MPC		2.2
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.76
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-118627631;