rs1057519475
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001453.3(FOXC1):c.316C>T(p.Gln106Ter) 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: 31)
Consequence
FOXC1
NM_001453.3 stop_gained
NM_001453.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.33
Genes affected
FOXC1 (HGNC:3800): (forkhead box C1) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]
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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 86 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-1610761-C-T is Pathogenic according to our data. Variant chr6-1610761-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXC1 | NM_001453.3 | c.316C>T | p.Gln106Ter | stop_gained | 1/1 | ENST00000645831.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXC1 | ENST00000645831.2 | c.316C>T | p.Gln106Ter | stop_gained | 1/1 | NM_001453.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Axenfeld-Rieger syndrome type 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2018 | For these reasons, this variant has been classified as Pathogenic. Different truncations (p.Gln120*, Leu240Valfs*65, p.Ser320Argfs*81) that lie downstream of this variant have been determined to be pathogenic (PMID: 20881294, 16638984, 18498376, 11782474). This suggests that deletion of this region of the FOXC1 protein is causative of disease. Experimental studies have shown that this nonsense change results in decreased protein half-life and increased transactivation (PMID: 25786029). This variant has been observed to segregate with Axenfeld-Rieger syndrome in a family (PMID: 28513611) and has also been observed in individuals affected with Axenfeld-Rieger syndrome (PMID: 20881294) or with bilateral primary congenital glaucoma (PMID: 25786029). ClinVar contains an entry for this variant (Variation ID: 375424). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Gln106*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 448 amino acids (~80%) of the FOXC1 protein. - |
Pathogenic, no assertion criteria provided | clinical testing | Genetics and Molecular Pathology, SA Pathology | Sep 19, 2014 | Non-sense codon introduces premature terminating codon (PTC) effecting functional haploinufficiency; clinical significance consistent with FOXC1 PTC variants found upstream and down stream of this position - each regarded as pathogenic in published literature. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2021 | Published functional studies demonstrate a a hypermorphic effect of the Q106X variant, along with decreased protein stability and protein mis-localization; Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 448 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32224865, 20881294, 25786029, 30514661, 28513611, 28432732) - |
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
Uncertain
D
MutationTaster
Benign
D
Vest4
GERP RS
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