14-70642437-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015351.2(TTC9):c.308C>T(p.Pro103Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P103A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TTC9 NM_015351.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

TTC9 (HGNC:20267): (tetratricopeptide repeat domain 9) This gene encodes a protein that contains three tetratricopeptide repeats. The gene has been shown to be hormonally regulated in breast cancer cells and may play a role in cancer cell invasion and metastasis. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113170624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC9	NM_015351.2	c.308C>T	p.Pro103Leu	missense_variant	1/3	ENST00000256367.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC9	ENST00000256367.3	c.308C>T	p.Pro103Leu	missense_variant	1/3	1	NM_015351.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 31

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

Dec 12, 2023

The c.308C>T (p.P103L) alteration is located in exon 1 (coding exon 1) of the TTC9 gene. This alteration results from a C to T substitution at nucleotide position 308, causing the proline (P) at amino acid position 103 to be replaced by a leucine (L). 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	0.078
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	18
Dann	Benign	0.86
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.036
Sift	Benign	0.24	T
Sift4G	Benign	0.32	T
Polyphen		0.76	P
Vest4		0.072
MutPred		0.24		Gain of catalytic residue at A107 (P = 0.0504);
MVP		0.22
MPC		0.64
ClinPred		0.26	T
GERP RS		3.4
Varity_R		0.061
gMVP		0.21

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: chr14-71109154; COSMIC: COSV56448610; COSMIC: COSV56448610;