rs398123611

chr6-1611567-G-GGGCGGCchr6-1611567-G-GGGCGGCGGCchr6-1611567-GGGCGGCGGC-Gchr6-1611567-GGGC-Gchr6-1611567-G-GGGCchr6-1611567-G-GGGCGGCGGCGGCGGCchr6-1611567-G-GGGCGGCGGCGGCchr6-1611567-GGGCGGC-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BS1_Supporting BS2

The NM_001453.3(FOXC1):c.1136_1141dup(p.Gly379_Gly380dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,142,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: FOXC1 NM_001453.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420

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 -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001453.3
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000334 (49/146526) while in subpopulation EAS AF= 0.00186 (9/4834). AF 95% confidence interval is 0.000971. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 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 GnomAd at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3	c.1136_1141dup	p.Gly379_Gly380dup	inframe_insertion	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.1136_1141dup	p.Gly379_Gly380dup	inframe_insertion	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 49 AN: 146424 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000678

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00186

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000334

Gnomad OTH AF: 0.000497

GnomAD3 exomes AF: 0.0000737 AC: 1 AN: 13566 Hom.: 0 AF XY: 0.000113 AC XY: 1 AN XY: 8876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000516 AC: 514 AN: 996234 Hom.: 0 Cov.: 32 AF XY: 0.000500 AC XY: 238 AN XY: 475960

Gnomad4 AFR exome AF: 0.000353

Gnomad4 AMR exome AF: 0.000173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000360

Gnomad4 SAS exome AF: 0.000618

Gnomad4 FIN exome AF: 0.0000662

Gnomad4 NFE exome AF: 0.000535

Gnomad4 OTH exome AF: 0.000571

GnomAD4 genome AF: 0.000334 AC: 49 AN: 146526 Hom.: 0 Cov.: 24 AF XY: 0.000379 AC XY: 27 AN XY: 71314

Gnomad4 AFR AF: 0.000367

Gnomad4 AMR AF: 0.0000677

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00186

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000334

Gnomad4 OTH AF: 0.000492

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

This variant, c.1136_1141dup, results in the insertion of 2 amino acid(s) of the FOXC1 protein (p.Gly379_Gly380dup), 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. -

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: rs76840944; hg19: chr6-1611802;