15-70052403-C-T

Variant names:

• chr15-70052403-C-T
• NM_001105192.3:c.2096G>A

Variant summary

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

The NM_001105192.3(TLE3):​c.2096G>A​(p.Cys699Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.81

Genes affected

TLE3 (HGNC:11839): (TLE family member 3, transcriptional corepressor) This gene encodes a transcriptional co-repressor protein that belongs to the transducin-like enhancer family of proteins. The members of this family function in the Notch signaling pathway that regulates determination of cell fate during development. Expression of this gene has been associated with a favorable outcome to chemotherapy with taxanes for ovarian carcinoma. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE3	NM_001105192.3	c.2096G>A	p.Cys699Tyr	missense_variant	Exon 18 of 20	ENST00000451782.7	NP_001098662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE3	ENST00000451782.7	c.2096G>A	p.Cys699Tyr	missense_variant	Exon 18 of 20	5	NM_001105192.3	ENSP00000394717.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

TLE3-related condition Uncertain:1

Jul 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TLE3 c.2105G>A variant is predicted to result in the amino acid substitution p.Cys702Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;.;T;T;.;.;.;T;T;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-10	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.;D;D;.;.;.;D;.;.
Vest4		0.76
MutPred		0.46		Gain of ubiquitination at K707 (P = 0.1191);Gain of ubiquitination at K707 (P = 0.1191);.;.;.;Gain of ubiquitination at K707 (P = 0.1191);.;.;.;.;.;.;.;.;.;
MVP		0.45
MPC		3.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.98

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: chr15-70344742;