Variant chr1-47416328-A-AG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_012186.3(FOXE3):c.14dup(p.Ser5ArgfsTer280) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,210,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

FOXE3
NM_012186.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.294

Variant links:

Genes affected

FOXE3 (HGNC:3808): (forkhead box E3) This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. The protein encoded functions as a lens-specific transcription factor and plays an important role in vertebrate lens formation. Mutations in this gene are associated with anterior segment mesenchymal dysgenesis and congenital primary aphakia. [provided by RefSeq, Dec 2009]

FOXE3 links:

LINC01389 (HGNC:):

LINC01389 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 43 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXE3	NM_012186.3 linkuse as main transcript	c.14dup	p.Ser5ArgfsTer280	frameshift_variant	1/1	ENST00000335071.4
LINC01389	NR_126355.1 linkuse as main transcript	n.29-6428_29-6427insC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXE3	ENST00000335071.4 linkuse as main transcript	c.14dup	p.Ser5ArgfsTer280	frameshift_variant	1/1		NM_012186.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000165

AC:

AN:

1210768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

593318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The c.14dupG variant, located in coding exon 1 of the FOXE3 gene, results from a duplication of G at nucleotide position 14, causing a translational frameshift with a predicted alternate stop codon (p.S5Rfs*280). This alteration is not expected to trigger nonsense-mediated mRNA decay and impacts greater than 50% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Although biallelic loss of function of FOXE3 has been associated with autosomal recessive FOXE3-related ocular development disorder, haploinsufficiency of FOXE3 has not been established as a mechanism of disease for autosomal dominant FOXE3-related ocular development disorder. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive FOXE3-related ocular development disorder when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant FOXE3-related ocular development disorder is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over