15-70057599-T-C

Variant names:

• chr15-70057599-T-C
• rs1389580599
• NM_001105192.3:c.1111A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001105192.3(TLE3):​c.1111A>G​(p.Met371Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,443,682 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.089223444).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE3	NM_001105192.3	c.1111A>G	p.Met371Val	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.1111A>G	p.Met371Val	missense_variant	Exon 13 of 20	5	NM_001105192.3	ENSP00000394717.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1443682 Hom.: 0 Cov.: 33 AF XY: 0.00000558 AC XY: 4 AN XY: 716566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1120A>G (p.M374V) alteration is located in exon 13 (coding exon 13) of the TLE3 gene. This alteration results from a A to G substitution at nucleotide position 1120, causing the methionine (M) at amino acid position 374 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	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Benign	0.63
DEOGEN2	Benign	0.16	T;T;.;T;T;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.92	N;.;.;.;.;.;.;.;.;.;.;.;N;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.28	N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.92	T;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;B;.;B;B;.;.;B;.;.
Vest4		0.31
MutPred		0.39		Loss of disorder (P = 0.0346);Loss of disorder (P = 0.0346);.;.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0346);.;
MVP		0.043
MPC		0.48
ClinPred		0.28	T
GERP RS		4.2
Varity_R		0.079
gMVP		0.52

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: rs1389580599; hg19: chr15-70349938;