6-1611567-GGGCGGCGGC-GGGCGGCGGCGGCGGCGGC

Variant names:

• chr6-1611574-GG-GGCGGCGGCG
• NM_001453.3:c.1131_1138dupCGGCGGCG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001453.3(FOXC1):​c.1131_1138dupCGGCGGCG​(p.Gly380AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G380G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXC1 NM_001453.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	NM_001453.3	MANE Select	c.1131_1138dupCGGCGGCG	p.Gly380AlafsTer24	frameshift	Exon 1 of 1	NP_001444.2	W6CJ52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	ENST00000645831.2	MANE Select	c.1131_1138dupCGGCGGCG	p.Gly380AlafsTer24	frameshift	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-1611809;