NM_001453.3:c.1051G>C

Variant names:

• chr6-1611496-G-C
• rs897755884
• NM_001453.3:c.1051G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001453.3(FOXC1):​c.1051G>C​(p.Gly351Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G351S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.97
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34612402).

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.1051G>C	p.Gly351Arg	missense	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.1051G>C	p.Gly351Arg	missense	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1224524 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 602120

African (AFR) AF: 0.00 AC: 0 AN: 24620

American (AMR) AF: 0.00 AC: 0 AN: 21874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20114

East Asian (EAS) AF: 0.00 AC: 0 AN: 24714

South Asian (SAS) AF: 0.00 AC: 0 AN: 60306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 991588

Other (OTH) AF: 0.00 AC: 0 AN: 48756

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Axenfeld-Rieger syndrome type 3 (1)
-	1	-	Axenfeld-Rieger syndrome type 3;C5975707:Anterior segment dysgenesis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Benign	0.16	T
Sift4G	Uncertain	0.041	D
Polyphen		0.43	B
Vest4		0.073
MutPred		0.26		Gain of helix (P = 0.062)
MVP		0.84
ClinPred		0.73	D
GERP RS		0.95
Varity_R		0.091
gMVP		0.28
Mutation Taster		=88/12	polymorphism

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: rs897755884; hg19: chr6-1611731;