6-80038006-G-T

Variant names:

• chr6-80038006-G-T
• rs1057520011
• NM_003318.5:c.2089G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003318.5(TTK):​c.2089G>T​(p.Asp697Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTK NM_003318.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.96
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003318.5. 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
	TTK	NM_003318.5	MANE Select	c.2089G>T	p.Asp697Tyr	missense	Exon 18 of 22	NP_003309.2
	TTK	NM_001438341.1		c.2089G>T	p.Asp697Tyr	missense	Exon 18 of 22	NP_001425270.1
	TTK	NM_001166691.2		c.2086G>T	p.Asp696Tyr	missense	Exon 18 of 22	NP_001160163.1	P33981-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTK	ENST00000369798.7	TSL:1 MANE Select	c.2089G>T	p.Asp697Tyr	missense	Exon 18 of 22	ENSP00000358813.2	P33981-1
	TTK	ENST00000936248.1		c.2125G>T	p.Asp709Tyr	missense	Exon 18 of 22	ENSP00000606307.1
	TTK	ENST00000936244.1		c.2107G>T	p.Asp703Tyr	missense	Exon 18 of 22	ENSP00000606303.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458494 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725592

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

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110100

Other (OTH) AF: 0.00 AC: 0 AN: 60198

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.0	L
PhyloP100		9.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.41		Loss of solvent accessibility (P = 0.0052)
MVP		0.80
MPC		0.57
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.86
gMVP		0.85
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1057520011; hg19: chr6-80747723; COSMIC: COSV57887607;