4-108079592-C-A

Variant names:

• chr4-108079592-C-A
• rs146861754
• NM_016269.5:c.745G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016269.5(LEF1):​c.745G>T​(p.Gly249Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G249D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LEF1 NM_016269.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• Publications: 6 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016269.5. 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
	LEF1	NM_016269.5	MANE Select	c.745G>T	p.Gly249Cys	missense	Exon 7 of 12	NP_057353.1	Q9UJU2-1
	LEF1	NM_001130714.3		c.661G>T	p.Gly221Cys	missense	Exon 6 of 10	NP_001124186.1	Q9UJU2-6
	LEF1	NM_001130713.3		c.661G>T	p.Gly221Cys	missense	Exon 6 of 11	NP_001124185.1	Q9UJU2-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEF1	ENST00000265165.6	TSL:1 MANE Select	c.745G>T	p.Gly249Cys	missense	Exon 7 of 12	ENSP00000265165.1	Q9UJU2-1
	LEF1	ENST00000379951.6	TSL:1	c.661G>T	p.Gly221Cys	missense	Exon 6 of 10	ENSP00000369284.2	Q9UJU2-6
	LEF1	ENST00000438313.6	TSL:1	c.661G>T	p.Gly221Cys	missense	Exon 6 of 11	ENSP00000406176.2	Q9UJU2-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.57
Sift	Benign	0.036	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.22		Loss of glycosylation at P251 (P = 0.0088)
MVP		0.90
MPC		0.64
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.62
Mutation Taster		=24/76	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: rs146861754; hg19: chr4-109000748;