rs897755884

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-1611496-G-A
• chr6-1611496-G-C
• chr6-1611496-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001453.3(FOXC1):​c.1051G>A​(p.Gly351Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000163 in 1,224,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G351R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 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=0.19723135).

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>A	p.Gly351Ser	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>A	p.Gly351Ser	missense	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1224522 Hom.: 0 Cov.: 31 AF XY: 0.00000166 AC XY: 1 AN XY: 602118

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: 0.0000166 AC: 1 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: 0.00000101 AC: 1 AN: 991586

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Axenfeld-Rieger syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.31
Sift	Benign	0.52	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.032
MutPred		0.18		Gain of glycosylation at G351 (P = 0.0076)
MVP		0.72
ClinPred		0.49	T
GERP RS		0.95
Varity_R		0.088
gMVP		0.22
Mutation Taster		=87/13	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;