rs1304168924

Variant names:

• chr15-70056352-G-A
• rs1304168924
• NM_001105192.3:c.1274C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-70056352-G-A
• chr15-70056352-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001105192.3(TLE3):​c.1274C>T​(p.Pro425Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. P425Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TLE3 NM_001105192.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29677078).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE3	NM_001105192.3	c.1274C>T	p.Pro425Leu	missense_variant	Exon 14 of 20	ENST00000451782.7	NP_001098662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE3	ENST00000451782.7	c.1274C>T	p.Pro425Leu	missense_variant	Exon 14 of 20	5	NM_001105192.3	ENSP00000394717.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247758 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000411 AC: 6 AN: 1461016 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726832

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52894

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;T;.;T;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.080
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;.;.;L;.;.;.;.;.;.;.;.;.
PhyloP100		3.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.037	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.17	B;.;B;.;.;B;.;B;B;.;.;.;B;.;.
Vest4		0.55
MutPred		0.32		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);.;.;.;Loss of sheet (P = 0.0084);.;.;.;.;.;.;.;.;.;
MVP		0.13
MPC		0.53
ClinPred		0.76	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.26
Mutation Taster		=68/32	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: rs1304168924; hg19: chr15-70348691; COSMIC: COSV58173251; COSMIC: COSV58173251;