Genetic Variant NM_012186.3:c.3G>T (chr1-47416318-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_012186.3(FOXE3):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXE3
NM_012186.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0610

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 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 7 codons. Genomic position: 47416334. Lost 0.020 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012186.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	NM_012186.3	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-6417C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 1	ENSP00000334472.2	Q13461
LINC01389	ENST00000828805.1		n.207+17045C>A		intron	N/A
LINC01389	ENST00000828806.1		n.92+913C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1192408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

582512

African (AFR)

AF:

0.00

AC:

AN:

24816

American (AMR)

AF:

0.00

AC:

AN:

19502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18912

East Asian (EAS)

AF:

0.00

AC:

AN:

26236

South Asian (SAS)

AF:

0.00

AC:

AN:

51146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3328

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

974704

Other (OTH)

AF:

0.00

AC:

AN:

47672

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Benign

-0.26

CADD

Benign

7.3

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.076

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.092

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.36

PhyloP100

0.061

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

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.83

gMVP

0.37

Mutation Taster

=181/19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over