chr15-70057655-G-C

Variant names:

• chr15-70057655-G-C
• rs759781735
• NM_001105192.3:c.1055C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001105192.3(TLE3):​c.1055C>G​(p.Ser352Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,104 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S352L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.43
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105192.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE3	NM_001105192.3	MANE Select	c.1055C>G	p.Ser352Trp	missense	Exon 13 of 20	NP_001098662.1	Q04726-5
	TLE3	NM_001438147.1		c.1085C>G	p.Ser362Trp	missense	Exon 13 of 20	NP_001425076.1
	TLE3	NM_001438148.1		c.1085C>G	p.Ser362Trp	missense	Exon 13 of 20	NP_001425077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE3	ENST00000451782.7	TSL:5 MANE Select	c.1055C>G	p.Ser352Trp	missense	Exon 13 of 20	ENSP00000394717.3	Q04726-5
	TLE3	ENST00000558939.5	TSL:1	c.1064C>G	p.Ser355Trp	missense	Exon 13 of 20	ENSP00000452871.1	Q04726-1
	TLE3	ENST00000558379.5	TSL:1	c.1064C>G	p.Ser355Trp	missense	Exon 13 of 20	ENSP00000453435.1	Q04726-6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416104 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 701338

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 38822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 37968

South Asian (SAS) AF: 0.00 AC: 0 AN: 81490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4782

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1094988

Other (OTH) AF: 0.00 AC: 0 AN: 59014

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Benign	0.044	D
Sift4G	Uncertain	0.016	D
Polyphen		0.61	P
Vest4		0.61
MutPred		0.44		Loss of sheet (P = 0.0043)
MVP		0.29
MPC		1.4
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759781735; hg19: chr15-70349994;