Variant rs76840944 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2

The NM_001453.3(FOXC1):c.1133_1141del(p.Gly378_Gly380del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,142,682 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00019 ( 3 hom. )

Consequence

FOXC1
NM_001453.3 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 sas. gnomad4_exome allele frequency = 0.000188 (187/996256) while in subpopulation SAS AF= 0.000882 (20/22672). AF 95% confidence interval is 0.000584. There are 3 homozygotes in gnomad4_exome. There are 82 alleles in male gnomad4_exome 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 GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3 linkuse as main transcript	c.1133_1141del	p.Gly378_Gly380del	inframe_deletion	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2 linkuse as main transcript	c.1133_1141del	p.Gly378_Gly380del	inframe_deletion	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000341

AC:

AN:

146426

Hom.:

Cov.:

show subpopulations

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:

0.0000758

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000590

AC:

AN:

13566

Hom.:

AF XY:

0.000789

AC XY:

AN XY:

8876

show subpopulations

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:

0.00149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000460

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

187

AN:

996256

Hom.:

AF XY:

0.000172

AC XY:

AN XY:

475972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000505

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000882

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000189

Gnomad4 OTH exome

AF:

0.0000272

GnomAD4 genome

AF:

0.0000341

AC:

AN:

146426

Hom.:

Cov.:

AF XY:

0.0000562

AC XY:

AN XY:

71200

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000758

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Axenfeld-Rieger syndrome type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2022

This variant, c.1133_1141del, results in the deletion of 3 amino acid(s) of the FOXC1 protein (p.Gly378_Gly380del), but otherwise preserves the integrity of the reading frame. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with FOXC1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over