rs79691946

Variant names:

• chr6-1611334-C-T
• rs79691946
• NM_001453.3:c.889C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001453.3(FOXC1):​c.889C>T​(p.Pro297Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,419,488 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P297L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (182 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (169 hom.)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:2 B:5
• Conservation: PhyloP100: 1.69
• Publications: 16 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: Benign. The variant received -19 ACMG points.

• 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, Peters anomaly, Axenfeld anomaly, Axenfeld-Rieger syndrome type 3, aniridia, anterior segment dysgenesis 3, isolated aniridia, Axenfeld-Rieger syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017443299).
• BP6: Variant 6-1611334-C-T is Benign according to our data. Variant chr6-1611334-C-T is described in ClinVar as Benign. ClinVar VariationId is 30156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

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.889C>T	p.Pro297Ser	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.889C>T	p.Pro297Ser	missense	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4293 AN: 150208 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.000582

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000847

Gnomad OTH AF: 0.0257

GnomAD2 exomes AF: 0.00284 AC: 213 AN: 75104 AF XY: 0.00217

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.000460

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00310 AC: 3930 AN: 1269172 Hom.: 169 Cov.: 32 AF XY: 0.00269 AC XY: 1685 AN XY: 625620

African (AFR) AF: 0.110 AC: 2816 AN: 25548

American (AMR) AF: 0.00611 AC: 149 AN: 24390

Ashkenazi Jewish (ASJ) AF: 0.000329 AC: 7 AN: 21268

East Asian (EAS) AF: 0.0000389 AC: 1 AN: 25704

South Asian (SAS) AF: 0.000278 AC: 19 AN: 68386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31074

Middle Eastern (MID) AF: 0.0104 AC: 38 AN: 3642

European-Non Finnish (NFE) AF: 0.000532 AC: 541 AN: 1017846

Other (OTH) AF: 0.00700 AC: 359 AN: 51314

GnomAD4 genome AF: 0.0286 AC: 4301 AN: 150316 Hom.: 182 Cov.: 32 AF XY: 0.0271 AC XY: 1986 AN XY: 73418

African (AFR) AF: 0.0966 AC: 3991 AN: 41322

American (AMR) AF: 0.0126 AC: 191 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.000582 AC: 2 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9926

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000847 AC: 57 AN: 67292

Other (OTH) AF: 0.0255 AC: 53 AN: 2082

Alfa AF: 0.0209 Hom.: 12

Bravo AF: 0.0320

ExAC AF: 0.00247 AC: 189

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
1	-	1	not provided (2)
1	-	-	Anterior segment dysgenesis 3 (1)
-	-	1	Axenfeld-Rieger syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.19
Sift	Benign	0.17	T
Sift4G	Benign	0.65	T
Polyphen		0.26	B
Vest4		0.14
MVP		0.81
ClinPred		0.0048	T
GERP RS		-0.40
Varity_R		0.044
gMVP		0.32
Mutation Taster		=98/2	polymorphism (auto)

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: rs79691946; hg19: chr6-1611569;