9-81587696-G-C

Variant names:

• chr9-81587696-G-C
• rs766051918
• NM_005077.5:c.1962C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_005077.5(TLE1):​c.1962C>G​(p.His654Gln) 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 1,460,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TLE1 NM_005077.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192

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]

LOC105376106 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE1	NM_005077.5	c.1962C>G	p.His654Gln	missense_variant	Exon 17 of 20	ENST00000376499.8	NP_005068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE1	ENST00000376499.8	c.1962C>G	p.His654Gln	missense_variant	Exon 17 of 20	1	NM_005077.5	ENSP00000365682.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460584 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1962C>G (p.H654Q) alteration is located in exon 17 (coding exon 17) of the TLE1 gene. This alteration results from a C to G substitution at nucleotide position 1962, causing the histidine (H) at amino acid position 654 to be replaced by a glutamine (Q). 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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.35
Sift	Benign	0.040	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.75		Loss of sheet (P = 0.0817);
MVP		0.54
MPC		2.1
ClinPred		0.99	D
GERP RS		-4.7
Varity_R		0.61
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs766051918; hg19: chr9-84202611;