Variant chr1-47416318-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_012186.3(FOXE3):c.3G>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 1,343,496 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

FOXE3
NM_012186.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0610

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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXE3	NM_012186.3 linkuse as main transcript	c.3G>C	p.Met1?	start_lost	1/1	ENST00000335071.4
LINC01389	NR_126355.1 linkuse as main transcript	n.29-6417C>G		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.3G>C	p.Met1?	start_lost	1/1		NM_012186.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151088

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000671

AC:

AN:

1192408

Hom.:

Cov.:

AF XY:

0.00000687

AC XY:

AN XY:

582512

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:

0.00000821

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73660

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:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 17, 2023

Variant summary: FOXE3 c.3G>C (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream, in-frame ATG start site is at codon 7 (Exon 1), however, alternative FOXE3 transcripts have yet to be identified. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 51214 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3G>C in individuals affected with Aortic Aneurysm, Familial Thoracic 11 and no experimental evidence demonstrating its impact on protein function have been reported in the literature. However, one ClinVar submitter has identified a start-loss variant in at least one individual with clinical features of FOXE3-related disorders (Invitae). Additionally, the variant has a non-damaging PoStaL score (0.411 compared to 0.4815 which corresponds to a 95% specificity in the test set (Takata_2021)). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital primary aphakia;C1862839:Anterior segment dysgenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal dominant FOXE3-related conditions (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change affects the initiator methionine of the FOXE3 mRNA. The next in-frame methionine is located at codon 7. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Benign

-0.26

CADD

Benign

7.3

DANN

Benign

0.97

DEOGEN2

Benign

0.076

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.097

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.36

MutationTaster

Benign

1.0

PROVEAN

Benign

-0.65

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0030

Vest4

0.17

MutPred

0.96

Gain of catalytic residue at M1 (P = 0.0255);

MVP

0.67

ClinPred

0.097

GERP RS

1.6

Varity_R

0.83

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