6-1611782-ACGGCGGCGGCGGCGG-ACGGCGG

Variant names:

• chr6-1611782-ACGGCGGCGG-A
• rs398123612
• NM_001453.3:c.1353_1361delCGGCGGCGG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001453.3(FOXC1):​c.1353_1361delCGGCGGCGG​(p.Gly452_Gly454del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,440,766 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 19)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.10

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 6-1611782-ACGGCGGCGG-A is Benign according to our data. Variant chr6-1611782-ACGGCGGCGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 598622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00137 (196/143116) while in subpopulation AFR AF= 0.00475 (184/38712). AF 95% confidence interval is 0.00419. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.1353_1361delCGGCGGCGG	p.Gly452_Gly454del	disruptive_inframe_deletion	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.1353_1361delCGGCGGCGG	p.Gly452_Gly454del	disruptive_inframe_deletion	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 196 AN: 143038 Hom.: 1 Cov.: 19

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000409

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00203

GnomAD3 exomes AF: 0.000185 AC: 12 AN: 64810 Hom.: 0 AF XY: 0.000159 AC XY: 6 AN XY: 37658

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.000700

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000736

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 247 AN: 1297650 Hom.: 0 AF XY: 0.000159 AC XY: 102 AN XY: 639914

Gnomad4 AFR exome AF: 0.00557

Gnomad4 AMR exome AF: 0.000588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000353

Gnomad4 SAS exome AF: 0.0000865

Gnomad4 FIN exome AF: 0.0000602

Gnomad4 NFE exome AF: 0.0000627

Gnomad4 OTH exome AF: 0.000242

GnomAD4 genome AF: 0.00137 AC: 196 AN: 143116 Hom.: 1 Cov.: 19 AF XY: 0.00141 AC XY: 98 AN XY: 69634

Gnomad4 AFR AF: 0.00475

Gnomad4 AMR AF: 0.000409

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000154

Gnomad4 OTH AF: 0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXC1: BS1 -

May 19, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Sep 11, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FOXC1-related disorder Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Axenfeld-Rieger syndrome type 3 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123612; hg19: chr6-1612017;