rs79691946

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001453.3(FOXC1):c.889C>T(p.Pro297Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,419,488 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P297L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 182 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 169 hom. )

Consequence

FOXC1
NM_001453.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:2B:4

Conservation

PhyloP100: 1.69

Publications

16 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017443299).

BP6

Variant 6-1611334-C-T is Benign according to our data. Variant chr6-1611334-C-T is described in ClinVar as Benign. ClinVar VariationId is 30156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3 link	c.889C>T	p.Pro297Ser	missense_variant	Exon 1 of 1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2 link	c.889C>T	p.Pro297Ser	missense_variant	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4293

AN:

150208

Hom.:

179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.000582

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000847

Gnomad OTH

AF:

0.0257

GnomAD2 exomes

AF:

0.00284

AC:

213

AN:

75104

AF XY:

0.00217

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.00515

Gnomad ASJ exome

AF:

0.000460

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000691

Gnomad OTH exome

AF:

0.00461

GnomAD4 exome

AF:

0.00310

AC:

3930

AN:

1269172

Hom.:

169

Cov.:

AF XY:

0.00269

AC XY:

1685

AN XY:

625620

show subpopulations

African (AFR)

AF:

0.110

AC:

2816

AN:

25548

American (AMR)

AF:

0.00611

AC:

149

AN:

24390

Ashkenazi Jewish (ASJ)

AF:

0.000329

AC:

AN:

21268

East Asian (EAS)

AF:

0.0000389

AC:

AN:

25704

South Asian (SAS)

AF:

0.000278

AC:

AN:

68386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31074

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

3642

European-Non Finnish (NFE)

AF:

0.000532

AC:

541

AN:

1017846

Other (OTH)

AF:

0.00700

AC:

359

AN:

51314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

206

412

618

824

1030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0286

AC:

4301

AN:

150316

Hom.:

182

Cov.:

AF XY:

0.0271

AC XY:

1986

AN XY:

73418

show subpopulations

African (AFR)

AF:

0.0966

AC:

3991

AN:

41322

American (AMR)

AF:

0.0126

AC:

191

AN:

15106

Ashkenazi Jewish (ASJ)

AF:

0.000582

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9926

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000847

AC:

AN:

67292

Other (OTH)

AF:

0.0255

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

198

396

595

793

991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0209

Hom.:

Bravo

AF:

0.0320

ExAC

AF:

0.00247

AC:

189

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 17197537, 25093829, 21423868, 19626132, 19793056) -

Human Genetics School of Medicine of Albacete, Castilla-La Mancha University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:not provided

- -

not specified

Benign:2

Mar 23, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Anterior segment dysgenesis 3

Pathogenic:1

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Axenfeld-Rieger syndrome type 3

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.34

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.69

N;N

PhyloP100

1.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.19

Sift

Benign

0.17

T;.

Sift4G

Benign

0.65

T;.

Polyphen

0.26

B;B

Vest4

0.14

MVP

0.81

ClinPred

0.0048

GERP RS

-0.40

Varity_R

0.044

gMVP

0.32

Mutation Taster

=98/2

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over