NM_007005.6:c.988A>C

Variant names:

• chr9-79708169-A-C
• NM_007005.6:c.988A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007005.6(TLE4):​c.988A>C​(p.Thr330Pro) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLE4 NM_007005.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 0 publications found

Genes affected

TLE4 (HGNC:11840): (TLE family member 4, transcriptional corepressor) Predicted to enable transcription corepressor activity. Predicted to be involved in negative regulation of canonical Wnt signaling pathway. Predicted to act upstream of or within Wnt signaling pathway; cellular response to leukemia inhibitory factor; and negative regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057371736).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007005.6. 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
	TLE4	NM_007005.6	MANE Select	c.988A>C	p.Thr330Pro	missense	Exon 12 of 20	NP_008936.2
	TLE4	NM_001282748.2		c.1084A>C	p.Thr362Pro	missense	Exon 13 of 21	NP_001269677.1	Q04727-3
	TLE4	NM_001351541.2		c.1027A>C	p.Thr343Pro	missense	Exon 13 of 21	NP_001338470.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE4	ENST00000376552.8	TSL:1 MANE Select	c.988A>C	p.Thr330Pro	missense	Exon 12 of 20	ENSP00000365735.2	Q04727-1
	TLE4	ENST00000376537.8	TSL:1	c.1084A>C	p.Thr362Pro	missense	Exon 13 of 21	ENSP00000365720.4	Q04727-3
	TLE4	ENST00000376544.7	TSL:1	c.781A>C	p.Thr261Pro	missense	Exon 10 of 18	ENSP00000365727.4	Q04727-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		2.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.045
Sift	Benign	0.14	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.23		Loss of phosphorylation at T330 (P = 0.0042)
MVP		0.15
MPC		0.53
ClinPred		0.19	T
GERP RS		2.3
Varity_R		0.086
gMVP		0.24
Mutation Taster		=82/18	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

hg19: chr9-82323084;