rs571095192

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012186.3(FOXE3):c.929G>A(p.Gly310Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,355,330 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G310G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 12 hom. )

Consequence

FOXE3
NM_012186.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.250

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004429668).

BP6

Variant 1-47417244-G-A is Benign according to our data. Variant chr1-47417244-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 289293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47417244-G-A is described in Lovd as [Likely_benign]. Variant chr1-47417244-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00153 (232/152018) while in subpopulation AMR AF= 0.0111 (169/15284). AF 95% confidence interval is 0.0097. There are 2 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXE3	NM_012186.3 linkuse as main transcript	c.929G>A	p.Gly310Asp	missense_variant	1/1	ENST00000335071.4
LINC01389	NR_126355.1 linkuse as main transcript	n.29-7343C>T		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.929G>A	p.Gly310Asp	missense_variant	1/1		NM_012186.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

232

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00265

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00360

AC:

AN:

18914

Hom.:

AF XY:

0.00246

AC XY:

AN XY:

11812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00350

Gnomad NFE exome

AF:

0.000253

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.000557

AC:

670

AN:

1203312

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

318

AN XY:

586506

show subpopulations

Gnomad4 AFR exome

AF:

0.000125

Gnomad4 AMR exome

AF:

0.0207

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000398

Gnomad4 FIN exome

AF:

0.00165

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.00153

AC:

232

AN:

152018

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00265

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.0000695

Hom.:

Bravo

AF:

0.00208

ExAC

AF:

0.000472

AC:

Asia WGS

AF:

0.000868

AC:

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Congenital primary aphakia;C1862839:Anterior segment dysgenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2019

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

Uncertain

0.41

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.93

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.69

REVEL

Benign

0.25

Sift

Benign

0.25

Sift4G

Benign

0.12

Polyphen

0.68

Vest4

0.16

MVP

0.56

ClinPred

0.017

GERP RS

1.6

Varity_R

0.052

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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