dbSNP rs281865461: FOXE3:p.Gly196Asp (chr1-47416902-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012186.3(FOXE3):c.587G>A(p.Gly196Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000856 in 1,167,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G196A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

FOXE3
NM_012186.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10566887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE3	NM_012186.3 link	c.587G>A	p.Gly196Asp	missense_variant	Exon 1 of 1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1 link	n.29-7001C>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.587G>A	p.Gly196Asp	missense_variant	Exon 1 of 1	6	NM_012186.3	ENSP00000334472.2		Q13461

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.56e-7

AC:

AN:

1167790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

572206

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000455

AC:

AN:

21994

American (AMR)

AF:

0.00

AC:

AN:

11824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16802

East Asian (EAS)

AF:

0.00

AC:

AN:

21256

South Asian (SAS)

AF:

0.00

AC:

AN:

49834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3110

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

959032

Other (OTH)

AF:

0.00

AC:

AN:

44870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0028

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.10

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.43

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.0

PhyloP100

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.1

REVEL

Benign

0.27

Sift

Benign

0.21

Sift4G

Benign

0.22

Polyphen

0.0010

Vest4

0.14

MutPred

0.28

Gain of solvent accessibility (P = 0.0638);

MVP

0.42

ClinPred

0.22

GERP RS

-2.4

Varity_R

0.059

gMVP

0.25

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over