NM_005077.5:c.1573G>T

Variant names:

• chr9-81593033-C-A
• rs1829761636
• NM_005077.5:c.1573G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005077.5(TLE1):​c.1573G>T​(p.Asp525Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D525N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TLE1 NM_005077.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84
• Publications: 0 publications found

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]

TLE1 Gene-Disease associations (from GenCC):

• movement disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE1	NM_005077.5	c.1573G>T	p.Asp525Tyr	missense_variant	Exon 15 of 20	ENST00000376499.8	NP_005068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE1	ENST00000376499.8	c.1573G>T	p.Asp525Tyr	missense_variant	Exon 15 of 20	1	NM_005077.5	ENSP00000365682.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460482 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726226

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110878

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.55		Loss of disorder (P = 0.0714);
MVP		0.63
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.97
gMVP		0.53
Mutation Taster		=35/65	disease causing

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: rs1829761636; hg19: chr9-84207948;