chr6-1611567-G-GGGCGGCGGC

Variant names:

• chr6-1611567-G-GGGCGGCGGC
• rs76840944
• NM_001453.3:c.1133_1141dupGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001453.3(FOXC1):​c.1133_1141dupGCGGCGGCG​(p.Gly378_Gly380dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,142,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.420
• Publications: 6 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000955 (14/146528) while in subpopulation SAS AF = 0.00188 (9/4794). AF 95% confidence interval is 0.000979. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 14 AD gene.

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.1133_1141dupGCGGCGGCG	p.Gly378_Gly380dup	disruptive_inframe_insertion	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.1133_1141dupGCGGCGGCG	p.Gly378_Gly380dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes AF: 0.0000956 AC: 14 AN: 146426 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000678

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000412

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 106 AN: 996242 Hom.: 0 Cov.: 32 AF XY: 0.000118 AC XY: 56 AN XY: 475962

African (AFR) AF: 0.000101 AC: 2 AN: 19814

American (AMR) AF: 0.00 AC: 0 AN: 5788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11264

East Asian (EAS) AF: 0.000539 AC: 6 AN: 11126

South Asian (SAS) AF: 0.00203 AC: 46 AN: 22670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2442

European-Non Finnish (NFE) AF: 0.0000528 AC: 46 AN: 871236

Other (OTH) AF: 0.000163 AC: 6 AN: 36796

GnomAD4 genome AF: 0.0000955 AC: 14 AN: 146528 Hom.: 0 Cov.: 24 AF XY: 0.000154 AC XY: 11 AN XY: 71316

African (AFR) AF: 0.0000489 AC: 2 AN: 40870

American (AMR) AF: 0.0000677 AC: 1 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.000414 AC: 2 AN: 4836

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65952

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=87/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76840944; hg19: chr6-1611802;