9-81613484-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005077.5(TLE1):c.956C>T(p.Thr319Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TLE1 NM_005077.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

TLE1 (HGNC:11837): (TLE family member 1, transcriptional corepressor) Enables identical protein binding activity and transcription corepressor activity. Involved in negative regulation of I-kappaB kinase/NF-kappaB signaling; negative regulation of anoikis; and regulation of gene expression. Located in cytosol and nucleoplasm. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLE1	NM_005077.5	c.956C>T	p.Thr319Ile	missense_variant	12/20	ENST00000376499.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLE1	ENST00000376499.8	c.956C>T	p.Thr319Ile	missense_variant	12/20	1	NM_005077.5	P1
TLE1	ENST00000464999.1	c.305C>T	p.Thr102Ile	missense_variant	4/6	3
TLE1	ENST00000491534.5	c.362C>T	p.Thr121Ile	missense_variant	4/5	5
TLE1	ENST00000376484.2	c.38C>T	p.Thr13Ile	missense_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.956C>T (p.T319I) alteration is located in exon 12 (coding exon 12) of the TLE1 gene. This alteration results from a C to T substitution at nucleotide position 956, causing the threonine (T) at amino acid position 319 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.91	P
Vest4		0.80
MutPred		0.20		Loss of glycosylation at T319 (P = 0.0038);
MVP		0.43
MPC		1.3
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.65
gMVP		0.19

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-84228399;