6-1611567-G-GGGCGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001453.3(FOXC1):c.1136_1141dupGCGGCG(p.Gly379_Gly380dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,142,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

FOXC1
NM_001453.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.420

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 6-1611567-G-GGGCGGC is Benign according to our data. Variant chr6-1611567-G-GGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1419128.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000334 (49/146526) while in subpopulation EAS AF = 0.00186 (9/4834). AF 95% confidence interval is 0.000971. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3 link	c.1136_1141dupGCGGCG	p.Gly379_Gly380dup	disruptive_inframe_insertion	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.1136_1141dupGCGGCG	p.Gly379_Gly380dup	disruptive_inframe_insertion	Exon 1 of 1		NM_001453.3	ENSP00000493906.1		Q12948

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

146424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000368

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000678

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00186

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000334

Gnomad OTH

AF:

0.000497

GnomAD2 exomes

AF:

0.0000737

AC:

AN:

13566

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000516

AC:

514

AN:

996234

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

238

AN XY:

475960

show subpopulations

Gnomad4 AFR exome

AF:

0.000353

AC:

AN:

19812

Gnomad4 AMR exome

AF:

0.000173

AC:

AN:

5788

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

11264

Gnomad4 EAS exome

AF:

0.000360

AC:

AN:

11126

Gnomad4 SAS exome

AF:

0.000618

AC:

AN:

22672

Gnomad4 FIN exome

AF:

0.0000662

AC:

AN:

15106

Gnomad4 NFE exome

AF:

0.000535

AC:

466

AN:

871230

Gnomad4 Remaining exome

AF:

0.000571

AC:

AN:

36794

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

104

130

<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:

0.000334

AC:

AN:

146526

Hom.:

Cov.:

AF XY:

0.000379

AC XY:

AN XY:

71314

show subpopulations

Gnomad4 AFR

AF:

0.000367

AC:

0.000367017

AN:

0.000367017

Gnomad4 AMR

AF:

0.0000677

AC:

0.0000677323

AN:

0.0000677323

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00186

AC:

0.00186181

AN:

0.00186181

Gnomad4 SAS

AF:

0.000209

AC:

0.000208594

AN:

0.000208594

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000334

AC:

0.000333576

AN:

0.000333576

Gnomad4 OTH

AF:

0.000492

AC:

0.000491642

AN:

0.000491642

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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.:

107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Axenfeld-Rieger syndrome type 3

Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1136_1141dup, results in the insertion of 2 amino acid(s) of the FOXC1 protein (p.Gly379_Gly380dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FOXC1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FOXC1: BP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=87/13

polymorphism

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over