6-1611567-GGGCGGCGGC-GGGCGGCGGCGGC

Variant names:

• chr6-1611567-G-GGGC
• rs76840944
• NM_001453.3:c.1139_1141dupGCG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001453.3(FOXC1):​c.1139_1141dupGCG​(p.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 0.204 in 1,139,916 control chromosomes in the GnomAD database, including 26,099 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4474 hom., cov: 24)
  • Exomes 𝑓: 0.20 (21625 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: 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 -16 ACMG points.

• BP6: Variant 6-1611567-G-GGGC is Benign according to our data. Variant chr6-1611567-G-GGGC is described in ClinVar as Benign. ClinVar VariationId is 193213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.1139_1141dupGCG	p.Gly380dup	disruptive_inframe_insertion	Exon 1 of 1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.1139_1141dupGCG	p.Gly380dup	disruptive_inframe_insertion	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 32657 AN: 146364 Hom.: 4481 Cov.: 24

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.0483 AC: 655 AN: 13566 AF XY: 0.0519

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0509

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.0538

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.202 AC: 200308 AN: 993452 Hom.: 21625 Cov.: 32 AF XY: 0.199 AC XY: 94319 AN XY: 474342

African (AFR) AF: 0.0954 AC: 1886 AN: 19776

American (AMR) AF: 0.206 AC: 1188 AN: 5756

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 1765 AN: 11234

East Asian (EAS) AF: 0.538 AC: 5955 AN: 11066

South Asian (SAS) AF: 0.271 AC: 6124 AN: 22606

European-Finnish (FIN) AF: 0.141 AC: 2123 AN: 15018

Middle Eastern (MID) AF: 0.197 AC: 480 AN: 2436

European-Non Finnish (NFE) AF: 0.199 AC: 173061 AN: 868856

Other (OTH) AF: 0.210 AC: 7726 AN: 36704

GnomAD4 genome AF: 0.223 AC: 32661 AN: 146464 Hom.: 4474 Cov.: 24 AF XY: 0.232 AC XY: 16535 AN XY: 71288

African (AFR) AF: 0.120 AC: 4903 AN: 40854

American (AMR) AF: 0.296 AC: 4373 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 844 AN: 3386

East Asian (EAS) AF: 0.668 AC: 3230 AN: 4834

South Asian (SAS) AF: 0.357 AC: 1711 AN: 4790

European-Finnish (FIN) AF: 0.254 AC: 2210 AN: 8690

Middle Eastern (MID) AF: 0.214 AC: 62 AN: 290

European-Non Finnish (NFE) AF: 0.221 AC: 14594 AN: 65926

Other (OTH) AF: 0.224 AC: 456 AN: 2034

Alfa AF: 0.0802 Hom.: 107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Axenfeld-Rieger syndrome type 3 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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; COSMIC: COSV66515600;