chr4-108063660-G-C

Position:

• chr4-108063660-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016269.5(LEF1):​c.1169C>G​(p.Thr390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LEF1 NM_016269.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36

Genes affected

LEF1 (HGNC:6551): (lymphoid enhancer binding factor 1) This gene encodes a transcription factor belonging to a family of proteins that share homology with the high mobility group protein-1. The protein encoded by this gene can bind to a functionally important site in the T-cell receptor-alpha enhancer, thereby conferring maximal enhancer activity. This transcription factor is involved in the Wnt signaling pathway, and it may function in hair cell differentiation and follicle morphogenesis. Mutations in this gene have been found in somatic sebaceous tumors. This gene has also been linked to other cancers, including androgen-independent prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30763775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEF1	NM_016269.5	c.1169C>G	p.Thr390Arg	missense_variant	11/12	ENST00000265165.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEF1	ENST00000265165.6	c.1169C>G	p.Thr390Arg	missense_variant	11/12	1	NM_016269.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Mar 25, 2024

The c.1169C>G (p.T390R) alteration is located in exon 11 (coding exon 11) of the LEF1 gene. This alteration results from a C to G substitution at nucleotide position 1169, causing the threonine (T) at amino acid position 390 to be replaced by an arginine (R). 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	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.044
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.033	D;D;D
Sift4G	Benign	0.32	T;T;T
Polyphen		0.20	B;B;.
Vest4		0.50
MutPred		0.26		Gain of glycosylation at T390 (P = 0.0058);.;.;
MVP		0.87
MPC		1.6
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr4-108984816;