chr6-1610680-C-A

Variant names:

• chr6-1610680-C-A
• rs1554100945
• NM_001453.3:c.235C>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001453.3(FOXC1):​c.235C>A​(p.Pro79Thr) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P79Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.03
• Publications: 1 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: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001453.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-1610681-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2571241.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: -3.6526 (below the threshold of 3.09). GenCC associations: The gene is linked to Rieger anomaly, Axenfeld-Rieger syndrome type 3, anterior segment dysgenesis 3, isolated aniridia, Axenfeld-Rieger syndrome, Axenfeld anomaly, aniridia, Peters anomaly.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 6-1610680-C-A is Pathogenic according to our data. Variant chr6-1610680-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3236698.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	NM_001453.3	MANE Select	c.235C>A	p.Pro79Thr	missense	Exon 1 of 1	NP_001444.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	ENST00000645831.2	MANE Select	c.235C>A	p.Pro79Thr	missense	Exon 1 of 1	ENSP00000493906.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anterior segment dysgenesis 3 Pathogenic:1

Moosajee Lab, UCL Institute of Ophthalmology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.95		Loss of catalytic residue at P79 (P = 0.0152)
MVP		0.99
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
gMVP		0.93
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs1554100945; hg19: chr6-1610915;