dbSNP rs80358194: FOXE3:p.Cys240* (chr1-47417035-C-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_012186.3(FOXE3):c.720C>A(p.Cys240*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,321,262 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

FOXE3
NM_012186.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.205

Publications

13 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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.

PP5

Variant 1-47417035-C-A is Pathogenic according to our data. Variant chr1-47417035-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.720C>A	p.Cys240*	stop_gained	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-7134G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.720C>A	p.Cys240*	stop_gained	Exon 1 of 1	ENSP00000334472.2	Q13461
LINC01389	ENST00000828805.1		n.207+16328G>T		intron	N/A
LINC01389	ENST00000828806.1		n.92+196G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000162

AC:

AN:

43132

AF XY:

0.000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1171316

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

574360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22620

American (AMR)

AF:

0.00

AC:

AN:

13554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17156

East Asian (EAS)

AF:

0.00

AC:

AN:

22796

South Asian (SAS)

AF:

0.000390

AC:

AN:

51234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

967854

Other (OTH)

AF:

0.00

AC:

AN:

46002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.597

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149946

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41182

American (AMR)

AF:

0.00

AC:

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67148

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

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:

0.00

Hom.:

ExAC

AF:

0.000167

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital primary aphakia (5)

not provided (2)

Anterior segment dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.013

FATHMM_MKL

Benign

0.20

PhyloP100

0.20

Vest4

0.30

GERP RS

2.1

Mutation Taster

=23/177

disease causing (ClinVar)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over