chr4-108079592-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_016269.5(LEF1):c.745G>A(p.Gly249Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
LEF1
NM_016269.5 missense
NM_016269.5 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 4.89
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 33 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEF1 | NM_016269.5 | c.745G>A | p.Gly249Ser | missense_variant | 7/12 | ENST00000265165.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEF1 | ENST00000265165.6 | c.745G>A | p.Gly249Ser | missense_variant | 7/12 | 1 | NM_016269.5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151896Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251444Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135900
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461756Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727202
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151896Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74168
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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 submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The c.745G>A (p.G249S) alteration is located in exon 7 (coding exon 7) of the LEF1 gene. This alteration results from a G to A substitution at nucleotide position 745, causing the glycine (G) at amino acid position 249 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;D;P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at