chr9-81652232-T-G

Variant names:

• chr9-81652232-T-G
• rs2228173
• NM_005077.5:c.354A>C

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.354A>C​(p.Glu118Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TLE1 NM_005077.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• Publications: 21 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, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE1	NM_005077.5	MANE Select	c.354A>C	p.Glu118Asp	missense	Exon 6 of 20	NP_005068.2
	TLE1	NM_001303103.2		c.354A>C	p.Glu118Asp	missense	Exon 6 of 20	NP_001290032.1
	TLE1	NM_001303104.2		c.354A>C	p.Glu118Asp	missense	Exon 6 of 20	NP_001290033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE1	ENST00000376499.8	TSL:1 MANE Select	c.354A>C	p.Glu118Asp	missense	Exon 6 of 20	ENSP00000365682.3
	TLE1	ENST00000418319.5	TSL:5	c.354A>C	p.Glu118Asp	missense	Exon 6 of 9	ENSP00000391347.1
	TLE1	ENST00000376463.3	TSL:2	c.264A>C	p.Glu88Asp	missense	Exon 5 of 6	ENSP00000365646.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.056	T
Polyphen		0.58	P
Vest4		0.62
MutPred		0.84		Loss of disorder (P = 0.103)
MVP		0.70
MPC		0.64
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.68
gMVP		0.54
Mutation Taster		=254/46	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: rs2228173; hg19: chr9-84267147;