6-1611252-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_001453.3(FOXC1):c.807C>G(p.Ser269Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,429,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S269S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FOXC1
NM_001453.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.783

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: 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: Likely_benign. The variant received -6 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=0.20627597).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000174 (26/149730) while in subpopulation AMR AF = 0.00166 (25/15076). AF 95% confidence interval is 0.00115. There are 1 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 26 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	NM_001453.3	MANE Select	c.807C>G	p.Ser269Arg	missense	Exon 1 of 1	NP_001444.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	ENST00000645831.2	MANE Select	c.807C>G	p.Ser269Arg	missense	Exon 1 of 1	ENSP00000493906.1

Frequencies

GnomAD3 genomes

AF:

0.000174

AC:

AN:

149730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00166

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000386

AC:

AN:

77786

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000201

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000133

AC:

AN:

1279976

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

631584

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25774

American (AMR)

AF:

0.000237

AC:

AN:

25274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21434

East Asian (EAS)

AF:

0.00

AC:

AN:

25986

South Asian (SAS)

AF:

0.00

AC:

AN:

70040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3946

European-Non Finnish (NFE)

AF:

0.00000391

AC:

AN:

1023946

Other (OTH)

AF:

0.000135

AC:

AN:

51866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000174

AC:

AN:

149730

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

AN XY:

73060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40908

American (AMR)

AF:

0.00166

AC:

AN:

15076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67288

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000166

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Axenfeld-Rieger syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.32

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

PhyloP100

0.78

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.32

Sift

Benign

0.37

Sift4G

Benign

0.092

Polyphen

0.50

Vest4

0.19

MutPred

0.34

Loss of phosphorylation at S269 (P = 8e-04)

MVP

0.91

ClinPred

0.095

GERP RS

1.3

Varity_R

0.099

gMVP

0.50

Mutation Taster

=71/29

polymorphism

(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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over