15-70054512-G-C

Variant names:

• chr15-70054512-G-C
• rs114111473
• NM_001105192.3:c.1752C>G

Variant summary

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

The NM_001105192.3(TLE3):​c.1752C>G​(p.Asp584Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D584D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.520
• 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.1752C>G	p.Asp584Glu	missense	Exon 16 of 20	NP_001098662.1	Q04726-5
	TLE3	NM_001438147.1		c.1782C>G	p.Asp594Glu	missense	Exon 16 of 20	NP_001425076.1
	TLE3	NM_001438148.1		c.1767C>G	p.Asp589Glu	missense	Exon 16 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.1752C>G	p.Asp584Glu	missense	Exon 16 of 20	ENSP00000394717.3	Q04726-5
	TLE3	ENST00000558939.5	TSL:1	c.1761C>G	p.Asp587Glu	missense	Exon 16 of 20	ENSP00000452871.1	Q04726-1
	TLE3	ENST00000558379.5	TSL:1	c.1746C>G	p.Asp582Glu	missense	Exon 16 of 20	ENSP00000453435.1	Q04726-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461710 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.52
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.62		Loss of ubiquitination at K589 (P = 0.1037)
MVP		0.30
MPC		2.5
ClinPred		0.99	D
GERP RS		-9.7
Varity_R		0.72
gMVP		0.77
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs114111473; hg19: chr15-70346851;