NM_012186.3:c.423G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012186.3(FOXE3):c.423G>A(p.Lys141Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,609,320 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 29 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 17 hom. )

Consequence

FOXE3
NM_012186.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.517

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 1-47416738-G-A is Benign according to our data. Variant chr1-47416738-G-A is described in ClinVar as Benign. ClinVar VariationId is 260211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.517 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0092 (1387/150690) while in subpopulation AFR AF = 0.0324 (1341/41428). AF 95% confidence interval is 0.0309. There are 29 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE3	NM_012186.3 link	c.423G>A	p.Lys141Lys	synonymous_variant	Exon 1 of 1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1 link	n.29-6837C>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.423G>A	p.Lys141Lys	synonymous_variant	Exon 1 of 1	6	NM_012186.3	ENSP00000334472.2

Frequencies

GnomAD3 genomes

AF:

0.00918

AC:

1382

AN:

150582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00218

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000444

Gnomad OTH

AF:

0.00434

GnomAD2 exomes

AF:

0.00230

AC:

573

AN:

249146

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.0327

Gnomad AMR exome

AF:

0.00115

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000993

GnomAD4 exome

AF:

0.000884

AC:

1289

AN:

1458630

Hom.:

Cov.:

AF XY:

0.000717

AC XY:

520

AN XY:

725700

show subpopulations

African (AFR)

AF:

0.0329

AC:

1097

AN:

33296

American (AMR)

AF:

0.00131

AC:

AN:

44388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000930

AC:

AN:

85980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110198

Other (OTH)

AF:

0.00196

AC:

118

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

157

236

314

393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00920

AC:

1387

AN:

150690

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

626

AN XY:

73634

show subpopulations

African (AFR)

AF:

0.0324

AC:

1341

AN:

41428

American (AMR)

AF:

0.00217

AC:

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000444

AC:

AN:

67542

Other (OTH)

AF:

0.00429

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00506

Hom.:

Bravo

AF:

0.0104

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 21, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

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

Mar 12, 2020

GeneDx

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

Apr 29, 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

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.52

PromoterAI

0.0082

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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