chr4-108064359-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_016269.5(LEF1):ā€‹c.1142A>Gā€‹(p.Glu381Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,611,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

LEF1
NM_016269.5 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.63
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 -4 ACMG points.

BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LEF1NM_016269.5 linkuse as main transcriptc.1142A>G p.Glu381Gly missense_variant 10/12 ENST00000265165.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LEF1ENST00000265165.6 linkuse as main transcriptc.1142A>G p.Glu381Gly missense_variant 10/121 NM_016269.5 Q9UJU2-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152174
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251140
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135728
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459680
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726328
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152174
Hom.:
0
Cov.:
31
AF XY:
0.0000538
AC XY:
4
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.0000302

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 GeneticsDec 27, 2023The c.1142A>G (p.E381G) alteration is located in exon 10 (coding exon 10) of the LEF1 gene. This alteration results from a A to G substitution at nucleotide position 1142, causing the glutamic acid (E) at amino acid position 381 to be replaced by a glycine (G). 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
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;.;.;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Uncertain
0.59
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.6
L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-4.1
D;D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0030
D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
0.92
P;B;B;.
Vest4
0.51
MutPred
0.16
Gain of glycosylation at S386 (P = 0.0283);.;.;.;
MVP
0.88
MPC
2.4
ClinPred
0.98
D
GERP RS
4.5
Varity_R
0.44
gMVP
0.43

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: rs1201511307; hg19: chr4-108985515; API