chr15-70058156-T-C

Variant names:

• chr15-70058156-T-C
• rs746708122
• ENST00000558939.5:c.1054A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005078.4(TLE3):​c.1054A>G​(p.Ile352Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TLE3 NM_005078.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08780867).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005078.4. 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.1051+3A>G		splice_region intron	N/A	NP_001098662.1	Q04726-5
	TLE3	NM_005078.4		c.1054A>G	p.Ile352Val	missense	Exon 12 of 20	NP_005069.2	Q04726-1
	TLE3	NM_001282980.2		c.1054A>G	p.Ile352Val	missense	Exon 12 of 20	NP_001269909.1	Q04726-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE3	ENST00000558939.5	TSL:1	c.1054A>G	p.Ile352Val	missense	Exon 12 of 20	ENSP00000452871.1	Q04726-1
	TLE3	ENST00000558379.5	TSL:1	c.1054A>G	p.Ile352Val	missense	Exon 12 of 20	ENSP00000453435.1	Q04726-6
	TLE3	ENST00000451782.7	TSL:5 MANE Select	c.1051+3A>G		splice_region intron	N/A	ENSP00000394717.3	Q04726-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 249168 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461628 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111828

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.030	N
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
Polyphen		0.0020	B
Vest4		0.093
MutPred		0.41		Gain of catalytic residue at I352 (P = 0.0044)
MVP		0.068
MPC		0.39
ClinPred		0.12	T
GERP RS		4.2
Varity_R		0.040
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs746708122; hg19: chr15-70350495;