1-47416902-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012186.3(FOXE3):c.587G>C(p.Gly196Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 1,317,094 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G196R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0057 ( 25 hom. )

Consequence

FOXE3
NM_012186.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.04

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041297674).

BP6

Variant 1-47416902-G-C is Benign according to our data. Variant chr1-47416902-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00439 (656/149314) while in subpopulation NFE AF = 0.00672 (450/66956). AF 95% confidence interval is 0.00621. There are 4 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE3	NM_012186.3 link	c.587G>C	p.Gly196Ala	missense_variant	Exon 1 of 1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1 link	n.29-7001C>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXE3	ENST00000335071.4 link	c.587G>C	p.Gly196Ala	missense_variant	Exon 1 of 1	6	NM_012186.3	ENSP00000334472.2

Frequencies

GnomAD3 genomes

AF:

0.00440

AC:

656

AN:

149204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000852

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00167

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0145

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.00672

Gnomad OTH

AF:

0.00293

GnomAD2 exomes

AF:

0.00644

AC:

340

AN:

52812

AF XY:

0.00564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.00666

Gnomad OTH exome

AF:

0.00565

GnomAD4 exome

AF:

0.00566

AC:

6613

AN:

1167780

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

3156

AN XY:

572202

show subpopulations

African (AFR)

AF:

0.000591

AC:

AN:

21994

American (AMR)

AF:

0.00178

AC:

AN:

11824

Ashkenazi Jewish (ASJ)

AF:

0.000119

AC:

AN:

16802

East Asian (EAS)

AF:

0.00

AC:

AN:

21256

South Asian (SAS)

AF:

0.0000602

AC:

AN:

49834

European-Finnish (FIN)

AF:

0.0189

AC:

739

AN:

39064

Middle Eastern (MID)

AF:

0.000322

AC:

AN:

3110

European-Non Finnish (NFE)

AF:

0.00587

AC:

5629

AN:

959026

Other (OTH)

AF:

0.00457

AC:

205

AN:

44870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

371

741

1112

1482

1853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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

AF:

0.00439

AC:

656

AN:

149314

Hom.:

Cov.:

AF XY:

0.00464

AC XY:

338

AN XY:

72858

show subpopulations

African (AFR)

AF:

0.000849

AC:

AN:

41202

American (AMR)

AF:

0.00166

AC:

AN:

15028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.000196

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0145

AC:

138

AN:

9514

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00672

AC:

450

AN:

66956

Other (OTH)

AF:

0.00290

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

106

141

176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00503

Hom.:

Bravo

AF:

0.00354

ExAC

AF:

0.00203

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11159941, 26854927)

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FOXE3: BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 21, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 25, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital primary aphakia;C1862839:Anterior segment dysgenesis

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Feb 16, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.062

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.0

PhyloP100

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.16

REVEL

Benign

0.19

Sift

Benign

0.50

Sift4G

Benign

0.58

Vest4

0.13

ClinPred

0.027

GERP RS

-2.4

Varity_R

0.031

gMVP

0.20

Mutation Taster

=99/1

polymorphism

(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

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over