chr4-108163608-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016269.5(LEF1):ā€‹c.374A>Gā€‹(p.Tyr125Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

LEF1
NM_016269.5 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LEF1NM_016269.5 linkuse as main transcriptc.374A>G p.Tyr125Cys missense_variant 3/12 ENST00000265165.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LEF1ENST00000265165.6 linkuse as main transcriptc.374A>G p.Tyr125Cys missense_variant 3/121 NM_016269.5 Q9UJU2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461598
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 GeneticsJul 13, 2021The c.374A>G (p.Y125C) alteration is located in exon 3 (coding exon 3) of the LEF1 gene. This alteration results from a A to G substitution at nucleotide position 374, causing the tyrosine (Y) at amino acid position 125 to be replaced by a cysteine (C). 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
0.14
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.1
M;M;M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.0
D;D;D;D;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0030
D;D;D;D;D;D
Sift4G
Uncertain
0.046
D;D;D;D;.;T
Polyphen
0.12
B;D;D;.;.;.
Vest4
0.92
MutPred
0.62
Gain of glycosylation at Y125 (P = 2e-04);Gain of glycosylation at Y125 (P = 2e-04);Gain of glycosylation at Y125 (P = 2e-04);.;.;.;
MVP
0.93
MPC
0.69
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.57
gMVP
0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-109084764; API