Genetic Variant FOXC1:p.Gly451_Gly454dup (chr6-1611782-A-ACGGCGGCGGCGG) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001453.3(FOXC1):c.1350_1361dupCGGCGGCGGCGG(p.Gly451_Gly454dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G454G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 19)

Exomes 𝑓: 0.0000039 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXC1
NM_001453.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.613

Publications

15 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3 link	c.1350_1361dupCGGCGGCGGCGG	p.Gly451_Gly454dup	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.1350_1361dupCGGCGGCGGCGG	p.Gly451_Gly454dup	disruptive_inframe_insertion	Exon 1 of 1		NM_001453.3	ENSP00000493906.1		Q12948

Frequencies

GnomAD3 genomes

AF:

0.0000140

AC:

AN:

143040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000682

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:

0.0000154

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000385

AC:

AN:

1297676

Hom.:

Cov.:

AF XY:

0.00000469

AC XY:

AN XY:

639924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25844

American (AMR)

AF:

0.0000420

AC:

AN:

23830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22552

East Asian (EAS)

AF:

0.00

AC:

AN:

28298

South Asian (SAS)

AF:

0.0000144

AC:

AN:

69338

European-Finnish (FIN)

AF:

0.0000301

AC:

AN:

33252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4778

European-Non Finnish (NFE)

AF:

0.00000193

AC:

AN:

1036144

Other (OTH)

AF:

0.00

AC:

AN:

53640

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

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:

0.0000140

AC:

AN:

143118

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

69634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38712

American (AMR)

AF:

0.0000682

AC:

AN:

14668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

4712

South Asian (SAS)

AF:

0.00

AC:

AN:

4438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

64808

Other (OTH)

AF:

0.00

AC:

AN:

1982

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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Axenfeld-Rieger syndrome type 3;C5975707:Anterior segment dysgenesis 3

Uncertain:1

Feb 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.61

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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6-1611782-ACGGCGGCGGCGGCGG-ACGGCGGCGGCGGCGGCGGCGGCGGCGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over