NM_001453.3:c.35C>T
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001453.3(FOXC1):c.35C>T(p.Ser12Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 151,316 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S12T) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FOXC1
NM_001453.3 missense
NM_001453.3 missense
Scores
4
12
2
Clinical Significance
Conservation
PhyloP100: 5.20
Publications
0 publications found
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]
FOXC1 Gene-Disease associations (from GenCC):
- anterior segment dysgenesis 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
- Axenfeld-Rieger syndrome type 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- aniridiaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- Axenfeld anomalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Axenfeld-Rieger syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated aniridiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Peters anomalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Rieger anomalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: -3.6526 (below the threshold of 3.09). GenCC associations: The gene is linked to Rieger anomaly, Axenfeld-Rieger syndrome type 3, anterior segment dysgenesis 3, isolated aniridia, Axenfeld-Rieger syndrome, Axenfeld anomaly, aniridia, Peters anomaly.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.771
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001453.3. You can select a different transcript below to see updated ACMG assignments.
Frequencies
GnomAD3 genomes 0.00000661 AC: 1AN: 151316Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151316
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1340612Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 657504
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1340612
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
657504
African (AFR)
AF:
AC:
0
AN:
29264
American (AMR)
AF:
AC:
0
AN:
26844
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
20842
East Asian (EAS)
AF:
AC:
0
AN:
34950
South Asian (SAS)
AF:
AC:
0
AN:
69228
European-Finnish (FIN)
AF:
AC:
0
AN:
45466
Middle Eastern (MID)
AF:
AC:
0
AN:
3828
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1054968
Other (OTH)
AF:
AC:
0
AN:
55222
GnomAD4 genome 0.00000661 AC: 1AN: 151316Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 73896 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
151316
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
73896
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41300
American (AMR)
AF:
AC:
1
AN:
15214
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3462
East Asian (EAS)
AF:
AC:
0
AN:
5116
South Asian (SAS)
AF:
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
AC:
0
AN:
10298
Middle Eastern (MID)
AF:
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67802
Other (OTH)
AF:
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
Inborn genetic diseases (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 8e-04)
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
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
Publications
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