6-1611567-GGGCGGCGGC-GGGCGGC

Position:

• chr6-1611567-GGGCGGCGGC-GGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001453.3(FOXC1):​c.1139_1141delGCG​(p.Gly380del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,141,794 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00047 (468/995372) while in subpopulation MID AF= 0.000821 (2/2436). AF 95% confidence interval is 0.000438. There are 2 homozygotes in gnomad4_exome. There are 252 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.1139_1141delGCG	p.Gly380del	disruptive_inframe_deletion	1/1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.1139_1141delGCG	p.Gly380del	disruptive_inframe_deletion	1/1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 24 AN: 146422 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000206

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000258

Gnomad OTH AF: 0.000497

GnomAD3 exomes AF: 0.000590 AC: 8 AN: 13566 Hom.: 0 AF XY: 0.000676 AC XY: 6 AN XY: 8876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000596

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000613

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.000470 AC: 468 AN: 995372 Hom.: 2 AF XY: 0.000530 AC XY: 252 AN XY: 475402

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000520

Gnomad4 ASJ exome AF: 0.000267

Gnomad4 EAS exome AF: 0.000450

Gnomad4 SAS exome AF: 0.000265

Gnomad4 FIN exome AF: 0.000598

Gnomad4 NFE exome AF: 0.000476

Gnomad4 OTH exome AF: 0.000544

GnomAD4 genome AF: 0.000164 AC: 24 AN: 146422 Hom.: 0 Cov.: 24 AF XY: 0.000155 AC XY: 11 AN XY: 71196

Gnomad4 AFR AF: 0.000123

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000206

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000258

Gnomad4 OTH AF: 0.000497

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2018

- -

Axenfeld-Rieger syndrome type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This variant, c.1139_1141del, results in the deletion of 1 amino acid(s) of the FOXC1 protein (p.Gly380del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FOXC1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

FOXC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs76840944; hg19: chr6-1611802;