rs756196843

Positions:

• chr6-1610525-GCGCGGCGGC-G
• chr6-1610525-GCGCGGCGGC-GCGCGGCGGCCGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001453.3(FOXC1):​c.92_100del​(p.Ala31_Ala33del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000971 in 1,530,714 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00096 (4 hom.)
• Consequence: FOXC1 NM_001453.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.99

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001453.3.
• BP6: Variant 6-1610525-GCGCGGCGGC-G is Benign according to our data. Variant chr6-1610525-GCGCGGCGGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 469652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-1610525-GCGCGGCGGC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00107 (162/151780) while in subpopulation SAS AF= 0.00332 (16/4822). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 162 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3	c.92_100del	p.Ala31_Ala33del	inframe_deletion	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.92_100del	p.Ala31_Ala33del	inframe_deletion	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 151672 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000884

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00108 AC: 140 AN: 129070 Hom.: 1 AF XY: 0.00121 AC XY: 85 AN XY: 70048

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.000228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000994

Gnomad SAS exome AF: 0.00348

Gnomad FIN exome AF: 0.000137

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000793

GnomAD4 exome AF: 0.000960 AC: 1324 AN: 1378934 Hom.: 4 AF XY: 0.00104 AC XY: 709 AN XY: 679420

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000169

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.000916

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.00107 AC: 162 AN: 151780 Hom.: 1 Cov.: 31 AF XY: 0.000997 AC XY: 74 AN XY: 74216

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000884

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000365 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27463523, 18708620, 19626132) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 01, 2018

- -

Axenfeld-Rieger syndrome type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

FOXC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs756196843; hg19: chr6-1610760;