rs749960549

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_012186.3(FOXE3):c.410G>A(p.Gly137Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,458,434 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G137G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

FOXE3
NM_012186.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 2.96

Publications

4 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_012186.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE3	NM_012186.3 link	c.410G>A	p.Gly137Asp	missense_variant	Exon 1 of 1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1 link	n.29-6824C>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.410G>A	p.Gly137Asp	missense_variant	Exon 1 of 1	6	NM_012186.3	ENSP00000334472.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249082

AF XY:

0.0000222

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 FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1458434

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

725606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33308

American (AMR)

AF:

0.00

AC:

AN:

44364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.00

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1110040

Other (OTH)

AF:

0.0000830

AC:

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000596

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta

Pathogenic:1

Feb 08, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Congenital primary aphakia;C1862839:Anterior segment dysgenesis

Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 137 of the FOXE3 protein (p.Gly137Asp). This variant is present in population databases (rs749960549, gnomAD 0.009%). This missense change has been observed in individual(s) with aortic dilation (PMID: 26854927). ClinVar contains an entry for this variant (Variation ID: 375652). 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 not expected to disrupt FOXE3 protein function with a negative predictive value of 80%. 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. -

Aortic aneurysm, familial thoracic 11, susceptibility to

Other:1

Jan 06, 2018

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.4

PhyloP100

3.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.51

Sift

Benign

0.060

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.71

MutPred

0.35

Loss of catalytic residue at G137 (P = 0.0522);

MVP

0.59

ClinPred

0.82

GERP RS

3.3

PromoterAI

0.029

Neutral

(source)

Varity_R

0.61

gMVP

0.65

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over