chr1-47416547-G-A

Position:

chr1-47416547-G-A

Variant summary

Our verdict is Pathogenic. Variant got 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

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

Conservation

PhyloP100: 5.69

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 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, 7 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/exons	MANE	Protein	UniProt
FOXE3	NM_012186.3 linkuse as main transcript	c.232G>A	p.Ala78Thr	missense_variant	1/1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1 linkuse as main transcript	n.29-6646C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXE3	ENST00000335071.4 linkuse as main transcript	c.232G>A	p.Ala78Thr	missense_variant	1/1	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

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

220408

Hom.:

AF XY:

0.0000330

AC XY:

AN XY:

121036

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000196

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000535

AC:

AN:

149452

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

72930

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.0000666

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000891

Gnomad4 OTH

AF:

0.00

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: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2024	This variant is associated with the following publications: (PMID: 34046667, 30187164, 29314435, 34426522, 31589614, 35170016, 29136273) -

Congenital primary aphakia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics Department, University Hospital of Toulouse	Jun 01, 2017	- -
Pathogenic, no assertion criteria provided	research	Human Developmental Genetics Laboratory, Medical College of Wisconsin	May 01, 2021	- -

Congenital primary aphakia;C1862839:Anterior segment dysgenesis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 14, 2022

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). 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Nov 09, 2021

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

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

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

Varity_R

0.59

gMVP

0.37

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

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