NM_003318.5:c.1201G>C

Variant names:

• chr6-80022416-G-C
• rs1481343179
• NM_003318.5:c.1201G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003318.5(TTK):​c.1201G>C​(p.Ala401Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTK NM_003318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12
• Publications: 0 publications found

Genes affected

TTK (HGNC:12401): (TTK protein kinase) This gene encodes a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13975614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTK	NM_003318.5	c.1201G>C	p.Ala401Pro	missense_variant	Exon 11 of 22	ENST00000369798.7	NP_003309.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTK	ENST00000369798.7	c.1201G>C	p.Ala401Pro	missense_variant	Exon 11 of 22	1	NM_003318.5	ENSP00000358813.2
TTK	ENST00000230510.7	c.1201G>C	p.Ala401Pro	missense_variant	Exon 11 of 22	2		ENSP00000230510.3
TTK	ENST00000509894.5	c.1201G>C	p.Ala401Pro	missense_variant	Exon 11 of 22	5		ENSP00000422936.1
TTK	ENST00000515751.1	n.325G>C		non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1201G>C (p.A401P) alteration is located in exon 11 (coding exon 10) of the TTK gene. This alteration results from a G to C substitution at nucleotide position 1201, causing the alanine (A) at amino acid position 401 to be replaced by a proline (P). 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	Benign	0.097
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L
PhyloP100		3.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.070	T;T;D
Sift4G	Benign	0.31	T;T;T
Polyphen		0.13	.;.;B
Vest4		0.23
MutPred		0.21		Gain of glycosylation at A401 (P = 0.025);Gain of glycosylation at A401 (P = 0.025);Gain of glycosylation at A401 (P = 0.025);
MVP		0.59
MPC		0.25
ClinPred		0.48	T
GERP RS		4.0
Varity_R		0.10
gMVP		0.30
Mutation Taster		=94/6	polymorphism

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: rs1481343179; hg19: chr6-80732133;