6-1610480-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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 (★).

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

Scores

4
12
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXC1NM_001453.3 linkuse as main transcriptc.35C>T p.Ser12Phe missense_variant 1/1 ENST00000645831.2 NP_001444.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXC1ENST00000645831.2 linkuse as main transcriptc.35C>T p.Ser12Phe missense_variant 1/1 NM_001453.3 ENSP00000493906 P1

Frequencies

GnomAD3 genomes
AF:
0.00000661
AC:
1
AN:
151316
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1340612
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
657504
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000661
AC:
1
AN:
151316
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
73896
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2024The c.35C>T (p.S12F) alteration is located in exon 1 (coding exon 1) of the FOXC1 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the serine (S) at amino acid position 12 to be replaced by a phenylalanine (F). 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
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;D
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
.;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.96
D
PROVEAN
Uncertain
-3.3
D;.
REVEL
Uncertain
0.57
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.014
D;.
Polyphen
1.0
D;D
Vest4
0.22
MutPred
0.37
Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);
MVP
0.97
ClinPred
0.99
D
GERP RS
2.4
Varity_R
0.52
gMVP
0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1762515001; hg19: chr6-1610715; API