rs35717904

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001453.3(FOXC1):c.*734A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 212,012 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 1 hom. )

Consequence

FOXC1
NM_001453.3 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1B:1

Conservation

PhyloP100: 2.48

Publications

5 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00351 (534/152332) while in subpopulation NFE AF = 0.00513 (349/68040). AF 95% confidence interval is 0.00469. There are 3 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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 534 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3 link	c.*734A>T		3_prime_UTR_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.*734A>T		3_prime_UTR_variant	Exon 1 of 1		NM_001453.3	ENSP00000493906.1		Q12948

Frequencies

GnomAD3 genomes

AF:

0.00351

AC:

534

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00384

GnomAD4 exome

AF:

0.00365

AC:

218

AN:

59680

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

AN XY:

27806

show subpopulations

African (AFR)

AF:

0.000536

AC:

AN:

1864

American (AMR)

AF:

0.00496

AC:

AN:

1210

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

2892

East Asian (EAS)

AF:

0.00

AC:

AN:

7236

South Asian (SAS)

AF:

0.00

AC:

AN:

414

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

14552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00538

AC:

148

AN:

27490

Other (OTH)

AF:

0.00560

AC:

AN:

3750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00351

AC:

534

AN:

152332

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

41560

American (AMR)

AF:

0.00490

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00513

AC:

349

AN:

68040

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00355

Hom.:

Bravo

AF:

0.00387

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

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

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FOXC1-related disorder

Benign:1

May 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

2.5

Mutation Taster

=39/61

disease causing (ClinVar)

(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