rs372857241

Positions:

• chr6-1610586-C-G
• chr6-1610586-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001453.3(FOXC1):​c.141C>G​(p.Tyr47Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-1610586-C-G is Pathogenic according to our data. Variant chr6-1610586-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 100687.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.141C>G	p.Tyr47Ter	stop_gained	1/1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.141C>G	p.Tyr47Ter	stop_gained	1/1		NM_001453.3	ENSP00000493906	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Human Genetics School of Medicine of Albacete, Castilla-La Mancha University

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- -

Axenfeld-Rieger syndrome type 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2020

For these reasons, this variant has been classified as Pathogenic. Different truncations (p.Gln120*, Leu240Valfs*65, p.Ser320Argfs*81) that lie downstream of this variant have been determined to be pathogenic (PMID: 20881294, 16638984, 18498376, 11782474, Invitae). This suggests that deletion of this region of the FOXC1 protein is causative of disease. Experimental studies have shown that this nonsense change decreases FOXC1 stability, but increases its transcriptional activation activity (PMID: 25786029). This variant has been reported in an individual affected with congenital glaucoma and her mother, who had juvenile open-angle glaucoma (PMID: 25786029). ClinVar contains an entry for this variant (Variation ID: 100687). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Tyr47*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 503 amino acids of the FOXC1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	D
Vest4		0.79
GERP RS		3.3

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

LitVar

Other links and lift over

dbSNP: rs372857241; hg19: chr6-1610821; COSMIC: COSV101083321; COSMIC: COSV101083321;