chr4-108163639-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_016269.5(LEF1):ā€‹c.343A>Cā€‹(p.Ile115Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.00011 ( 0 hom. )

Consequence

LEF1
NM_016269.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.95
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18036929).
BS2
High AC in GnomAdExome4 at 166 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LEF1NM_016269.5 linkuse as main transcriptc.343A>C p.Ile115Leu missense_variant 3/12 ENST00000265165.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LEF1ENST00000265165.6 linkuse as main transcriptc.343A>C p.Ile115Leu missense_variant 3/121 NM_016269.5 Q9UJU2-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251400
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000114
AC:
166
AN:
1461598
Hom.:
0
Cov.:
30
AF XY:
0.0000963
AC XY:
70
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000139
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2022The c.343A>C (p.I115L) alteration is located in exon 3 (coding exon 3) of the LEF1 gene. This alteration results from a A to C substitution at nucleotide position 343, causing the isoleucine (I) at amino acid position 115 to be replaced by a leucine (L). 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
0.11
BayesDel_addAF
Benign
0.0017
T
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
20
DANN
Benign
0.79
DEOGEN2
Benign
0.35
T;.;.;.;.;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.036
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.82
T;T;T;T;T;T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.18
T;T;T;T;T;T
MetaSVM
Uncertain
0.78
D
MutationAssessor
Benign
0.18
N;N;N;.;.;.
MutationTaster
Benign
0.98
D;D;D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
0.070
N;N;N;N;N;N
REVEL
Uncertain
0.47
Sift
Benign
1.0
T;T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;.;T
Polyphen
0.0
B;B;B;.;.;.
Vest4
0.47
MutPred
0.29
Gain of glycosylation at Y114 (P = 7e-04);Gain of glycosylation at Y114 (P = 7e-04);Gain of glycosylation at Y114 (P = 7e-04);.;.;.;
MVP
0.66
MPC
0.14
ClinPred
0.086
T
GERP RS
5.7
Varity_R
0.18
gMVP
0.38

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754959962; hg19: chr4-109084795; API