15-70050164-G-A

Variant names:

• chr15-70050164-G-A
• rs780171986
• NM_001105192.3:c.2243C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001105192.3(TLE3):​c.2243C>T​(p.Ala748Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058537543).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE3	NM_001105192.3	c.2243C>T	p.Ala748Val	missense_variant	Exon 20 of 20	ENST00000451782.7	NP_001098662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE3	ENST00000451782.7	c.2243C>T	p.Ala748Val	missense_variant	Exon 20 of 20	5	NM_001105192.3	ENSP00000394717.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249362 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461756 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2252C>T (p.A751V) alteration is located in exon 20 (coding exon 20) of the TLE3 gene. This alteration results from a C to T substitution at nucleotide position 2252, causing the alanine (A) at amino acid position 751 to be replaced by a valine (V). 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	0.092
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Benign	0.73
DEOGEN2	Benign	0.21	T;T;.;T;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.059	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;.;.;.;N;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.30	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.84	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;.;B;.;.;B;.;B;B;.;.;.;B;.;.
Vest4		0.13
MutPred		0.55		Loss of ubiquitination at K754 (P = 0.0504);Loss of ubiquitination at K754 (P = 0.0504);.;.;.;Loss of ubiquitination at K754 (P = 0.0504);.;.;.;.;.;.;.;.;.;
MVP		0.068
MPC		1.3
ClinPred		0.055	T
GERP RS		3.8
Varity_R		0.037
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs780171986; hg19: chr15-70342503;