15-70057530-G-T

Variant names:

• chr15-70057530-G-T
• rs773096656
• NM_001105192.3:c.1180C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001105192.3(TLE3):​c.1180C>A​(p.Pro394Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,454,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39753687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE3	NM_001105192.3	c.1180C>A	p.Pro394Thr	missense_variant	Exon 13 of 20	ENST00000451782.7	NP_001098662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE3	ENST00000451782.7	c.1180C>A	p.Pro394Thr	missense_variant	Exon 13 of 20	5	NM_001105192.3	ENSP00000394717.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454996 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1189C>A (p.P397T) alteration is located in exon 13 (coding exon 13) of the TLE3 gene. This alteration results from a C to A substitution at nucleotide position 1189, causing the proline (P) at amino acid position 397 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;.;T;T;.;.;.;D;T;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.7	D;.;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;.;D;T;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;T;D;D;T;D;T;T;D;D;T;T;D
Polyphen		0.64	P;.;D;.;.;D;.;B;P;.;.;B;.;.
Vest4		0.33
MutPred		0.65		Loss of catalytic residue at P396 (P = 0.0096);Loss of catalytic residue at P396 (P = 0.0096);.;.;.;.;.;.;.;.;.;.;Loss of catalytic residue at P396 (P = 0.0096);.;
MVP		0.44
MPC		0.62
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.59
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773096656; hg19: chr15-70349869;