rs104893741
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_023067.4(FOXL2):c.655C>T(p.Gln219Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FOXL2
NM_023067.4 stop_gained
NM_023067.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.15
Genes affected
FOXL2 (HGNC:1092): (forkhead box L2) This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-138946068-G-A is Pathogenic according to our data. Variant chr3-138946068-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXL2 | NM_023067.4 | c.655C>T | p.Gln219Ter | stop_gained | 1/1 | ENST00000648323.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXL2 | ENST00000648323.1 | c.655C>T | p.Gln219Ter | stop_gained | 1/1 | NM_023067.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1265594Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 622124
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1265594
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
622124
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Blepharophimosis, ptosis, and epicanthus inversus syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 03, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 24, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXL2 protein in which other variant(s) (p.His311Tyr) have been determined to be pathogenic (PMID: 30029625). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 4853). This premature translational stop signal has been observed in individuals with blepharophimosis, ptosis, and epicanthus inversus syndrome (PMID: 11175783, 30198434). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln219*) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 158 amino acid(s) of the FOXL2 protein. - |
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
0.90
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at