rs771039137

chr6-1611634-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001453.3(FOXC1):c.1189C>T(p.Leu397=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,319,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: FOXC1 NM_001453.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.439

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 6-1611634-C-T is Benign according to our data. Variant chr6-1611634-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 537392.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.439 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0003 (44/146816) while in subpopulation NFE AF= 0.000497 (33/66440). AF 95% confidence interval is 0.000363. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3	c.1189C>T	p.Leu397=	synonymous_variant	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.1189C>T	p.Leu397=	synonymous_variant	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes AF: 0.000300 AC: 44 AN: 146816 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000125

Gnomad AMI AF: 0.00223

Gnomad AMR AF: 0.000203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000497

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000406 AC: 6 AN: 14776 Hom.: 0 AF XY: 0.000522 AC XY: 5 AN XY: 9580

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000426 AC: 499 AN: 1172270 Hom.: 0 Cov.: 33 AF XY: 0.000410 AC XY: 234 AN XY: 570798

Gnomad4 AFR exome AF: 0.000131

Gnomad4 AMR exome AF: 0.000104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000497

Gnomad4 OTH exome AF: 0.000190

GnomAD4 genome AF: 0.000300 AC: 44 AN: 146816 Hom.: 0 Cov.: 32 AF XY: 0.000279 AC XY: 20 AN XY: 71630

Gnomad4 AFR AF: 0.000125

Gnomad4 AMR AF: 0.000203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000107

Gnomad4 NFE AF: 0.000497

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000298

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	13
Dann	Benign	0.96

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: rs771039137; hg19: chr6-1611869;