NM_001453.3:c.38T>C

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.38T>C(p.Leu13Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000134 in 1,493,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

FOXC1
NM_001453.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.13

Publications

0 publications found

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]

FOXC1 Gene-Disease associations (from GenCC):

anterior segment dysgenesis 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
Axenfeld-Rieger syndrome type 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
aniridia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Axenfeld anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Axenfeld-Rieger syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated aniridia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Peters anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Rieger anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FOXC1 links:

Genome browser will be placed here

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, 0.794

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.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	NM_001453.3	MANE Select	c.38T>C	p.Leu13Pro	missense	Exon 1 of 1	NP_001444.2	W6CJ52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	ENST00000645831.2	MANE Select	c.38T>C	p.Leu13Pro	missense	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

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

AF:

7.45e-7

AC:

AN:

1342550

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

658702

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29302

American (AMR)

AF:

0.00

AC:

AN:

27050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21000

East Asian (EAS)

AF:

0.00

AC:

AN:

34974

South Asian (SAS)

AF:

0.00

AC:

AN:

69678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3834

European-Non Finnish (NFE)

AF:

9.47e-7

AC:

AN:

1055860

Other (OTH)

AF:

0.00

AC:

AN:

55290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41236

American (AMR)

AF:

0.00

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000196

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67716

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.1

PhyloP100

5.1

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Benign

0.081

Polyphen

1.0

Vest4

0.44

MutPred

0.39

Gain of disorder (P = 0.0043)

MVP

0.98

ClinPred

1.0

GERP RS

3.3

Varity_R

0.80

gMVP

0.75

Mutation Taster

=12/88

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over