NM_001105192.3:c.2217G>A

Variant names:

• chr15-70050190-C-T
• rs35256928
• NM_001105192.3:c.2217G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001105192.3(TLE3):​c.2217G>A​(p.Ser739Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,836 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (26 hom.)
• Consequence: TLE3 NM_001105192.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.73
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-70050190-C-T is Benign according to our data. Variant chr15-70050190-C-T is described in ClinVar as Benign. ClinVar VariationId is 788450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00945 (1438/152202) while in subpopulation AFR AF = 0.0335 (1391/41524). AF 95% confidence interval is 0.032. There are 21 homozygotes in GnomAd4. There are 672 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1438 AD gene.

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.2217G>A	p.Ser739Ser	synonymous	Exon 20 of 20	NP_001098662.1	Q04726-5
	TLE3	NM_001438147.1		c.2247G>A	p.Ser749Ser	synonymous	Exon 20 of 20	NP_001425076.1
	TLE3	NM_001438148.1		c.2232G>A	p.Ser744Ser	synonymous	Exon 20 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.2217G>A	p.Ser739Ser	synonymous	Exon 20 of 20	ENSP00000394717.3	Q04726-5
	TLE3	ENST00000558939.5	TSL:1	c.2226G>A	p.Ser742Ser	synonymous	Exon 20 of 20	ENSP00000452871.1	Q04726-1
	TLE3	ENST00000558379.5	TSL:1	c.2211G>A	p.Ser737Ser	synonymous	Exon 20 of 20	ENSP00000453435.1	Q04726-6

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1436 AN: 152084 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00236 AC: 588 AN: 249246 AF XY: 0.00187

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000956 AC: 1398 AN: 1461634 Hom.: 26 Cov.: 30 AF XY: 0.000803 AC XY: 584 AN XY: 727112

African (AFR) AF: 0.0356 AC: 1190 AN: 33472

American (AMR) AF: 0.00141 AC: 63 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111818

Other (OTH) AF: 0.00157 AC: 95 AN: 60368

GnomAD4 genome AF: 0.00945 AC: 1438 AN: 152202 Hom.: 21 Cov.: 32 AF XY: 0.00903 AC XY: 672 AN XY: 74408

African (AFR) AF: 0.0335 AC: 1391 AN: 41524

American (AMR) AF: 0.00229 AC: 35 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00253 Hom.: 2

Bravo AF: 0.0109

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.2
DANN	Benign	0.73
PhyloP100		-5.7
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35256928; hg19: chr15-70342529;