chr6-1611397-CG-C

Variant names:

• chr6-1611397-CG-C
• rs1241813534
• NM_001453.3:c.957delG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001453.3(FOXC1):​c.957delG​(p.Ser320ArgfsTer81) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,299,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXC1 NM_001453.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.970
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 30 pathogenic variants in the truncated region.
• PP5: Variant 6-1611397-CG-C is Pathogenic according to our data. Variant chr6-1611397-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 537391.Status of the report is criteria_provided_single_submitter, 1 stars.

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.957delG	p.Ser320ArgfsTer81	frameshift	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.957delG	p.Ser320ArgfsTer81	frameshift	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150500 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000744 AC: 7 AN: 94046 AF XY: 0.0000553

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.000146

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.0000260

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 8 AN: 1299640 Hom.: 0 Cov.: 31 AF XY: 0.00000467 AC XY: 3 AN XY: 642448

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26150

American (AMR) AF: 0.0000722 AC: 2 AN: 27702

Ashkenazi Jewish (ASJ) AF: 0.0000455 AC: 1 AN: 21974

East Asian (EAS) AF: 0.00 AC: 0 AN: 26766

South Asian (SAS) AF: 0.0000277 AC: 2 AN: 72134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3742

European-Non Finnish (NFE) AF: 0.00000290 AC: 3 AN: 1036070

Other (OTH) AF: 0.00 AC: 0 AN: 52666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150500 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73434

African (AFR) AF: 0.00 AC: 0 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67386

Other (OTH) AF: 0.00 AC: 0 AN: 2068

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Axenfeld-Rieger syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=8/192	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1241813534; hg19: chr6-1611632;