rs73406891

Variant names:

• chr6-1612008-T-G
• rs73406891
• NM_001453.3:c.1563T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001453.3(FOXC1):​c.1563T>G​(p.Ser521Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,612,278 control chromosomes in the GnomAD database, including 404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (196 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (208 hom.)
• Consequence: FOXC1 NM_001453.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.33
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 6-1612008-T-G is Benign according to our data. Variant chr6-1612008-T-G is described in ClinVar as Benign. ClinVar VariationId is 167087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0969 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	NM_001453.3	MANE Select	c.1563T>G	p.Ser521Ser	synonymous	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.1563T>G	p.Ser521Ser	synonymous	Exon 1 of 1	ENSP00000493906.1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4437 AN: 152068 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0994

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.00777 AC: 1925 AN: 247688 AF XY: 0.00564

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00543

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000842

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00356 AC: 5202 AN: 1460102 Hom.: 208 Cov.: 37 AF XY: 0.00315 AC XY: 2290 AN XY: 726276

African (AFR) AF: 0.109 AC: 3659 AN: 33474

American (AMR) AF: 0.00611 AC: 272 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000883 AC: 76 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52524

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5764

European-Non Finnish (NFE) AF: 0.000607 AC: 675 AN: 1111706

Other (OTH) AF: 0.00736 AC: 444 AN: 60290

GnomAD4 genome AF: 0.0293 AC: 4452 AN: 152176 Hom.: 196 Cov.: 33 AF XY: 0.0277 AC XY: 2060 AN XY: 74400

African (AFR) AF: 0.0995 AC: 4127 AN: 41488

American (AMR) AF: 0.0130 AC: 199 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67996

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0146 Hom.: 90

Bravo AF: 0.0332

Asia WGS AF: 0.00751 AC: 27 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-3.3
Mutation Taster		=100/0	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: rs73406891; hg19: chr6-1612243;