6-1611782-ACGGCGGCGGCGGCGG-A

Variant names:

• chr6-1611782-ACGGCGGCGGCGGCGG-A
• rs398123612
• NM_001453.3:c.1347_1361delCGGCGGCGGCGGCGG

Variant summary

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

The NM_001453.3(FOXC1):​c.1347_1361delCGGCGGCGGCGGCGG​(p.Gly450_Gly454del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,297,672 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• Publications: 0 publications found

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

ACMG classification

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	c.1347_1361delCGGCGGCGGCGGCGG	p.Gly450_Gly454del	disruptive_inframe_deletion	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	c.1347_1361delCGGCGGCGGCGGCGG	p.Gly450_Gly454del	disruptive_inframe_deletion	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1297672 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 639922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25844

American (AMR) AF: 0.0000420 AC: 1 AN: 23830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22552

East Asian (EAS) AF: 0.00 AC: 0 AN: 28298

South Asian (SAS) AF: 0.00 AC: 0 AN: 69338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4778

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036140

Other (OTH) AF: 0.00 AC: 0 AN: 53640

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

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

Other links and lift over

dbSNP: rs398123612; hg19: chr6-1612017;