NM_012186.3:c.232G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_012186.3(FOXE3):c.232G>A(p.Ala78Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000451 in 1,574,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A78A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

FOXE3
NM_012186.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 5.69

Publications

5 publications found

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:50661): (long intergenic non-protein coding RNA 1389)

LINC01389 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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, 10 uncertain in NM_012186.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

PP5

Variant 1-47416547-G-A is Pathogenic according to our data. Variant chr1-47416547-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE3	NM_012186.3 link	c.232G>A	p.Ala78Thr	missense_variant	Exon 1 of 1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1 link	n.29-6646C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXE3	ENST00000335071.4 link	c.232G>A	p.Ala78Thr	missense_variant	Exon 1 of 1	6	NM_012186.3	ENSP00000334472.2		Q13461

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

149452

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000666

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:

0.0000891

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000363

AC:

AN:

220408

AF XY:

0.0000330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000977

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000508

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

1424776

Hom.:

Cov.:

AF XY:

0.0000508

AC XY:

AN XY:

708840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31510

American (AMR)

AF:

0.000121

AC:

AN:

41350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24906

East Asian (EAS)

AF:

0.00

AC:

AN:

37174

South Asian (SAS)

AF:

0.00

AC:

AN:

83544

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5136

European-Non Finnish (NFE)

AF:

0.0000522

AC:

AN:

1091880

Other (OTH)

AF:

0.00

AC:

AN:

58246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000535

AC:

AN:

149452

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

72930

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41016

American (AMR)

AF:

0.0000666

AC:

AN:

15004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5058

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

67358

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 09, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 34046667, 30187164, 29314435, 34426522, 31589614, 35170016, 29136273) -

Mar 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FOXE3 c.232G>A; p.Ala78Thr variant (rs377669670) is reported in both the homozygous and compound heterozygous states in individuals with FOXE3-related ocular disorders (Chesneau 2022, Plaisancie 2018, Reis 2021). This variant is also reported in ClinVar (Variation ID: 427852). It is observed in the general population with a low overall allele frequency of 0.004% (10/248542 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.862). Based on available information, this variant is considered to be likely pathogenic for autosomal recessive anterior segment dysgenesis 2. It is uncertain whether or not this variant would cause susceptibility to familial thoracic aortic aneurysm 11. References: Chesneau B et al. First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients. Clin Genet. 2022 May;101(5-6):494-506. PMID: 35170016. Plaisancie J et al. FOXE3 mutations: genotype-phenotype correlations. Clin Genet. 2018 Apr;93(4):837-845. PMID: 29136273. Reis LM et al. Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders. Hum Mol Genet. 2021 Aug 12;30(17):1591-1606. PMID: 34046667. -

Congenital primary aphakia

Pathogenic:2

Jun 01, 2017

Genetics Department, University Hospital of Toulouse

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2021

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Congenital primary aphakia;C1862839:Anterior segment dysgenesis

Pathogenic:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 78 of the FOXE3 protein (p.Ala78Thr). 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 missense change has been observed in individual(s) with autosomal recessive FOXE3-related conditions (PMID: 29136273, 34046667, 35170016). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 427852). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FOXE3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

The c.232G>A (p.A78T) alteration is located in exon 1 (coding exon 1) of the FOXE3 gene. This alteration results from a G to A substitution at nucleotide position 232, causing the alanine (A) at amino acid position 78 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.82

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

2.0

PhyloP100

5.7

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.50

MVP

0.88

ClinPred

0.73

GERP RS

3.1

PromoterAI

0.056

Neutral

(source)

Varity_R

0.59

gMVP

0.37

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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NM_012186.3:c.232G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over