rs104893741

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_023067.4(FOXL2):c.655C>T(p.Gln219*) variant causes a stop gained change. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005417057: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."".

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXL2
NM_023067.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 5.15

Publications

9 publications found

Variant links:

Genes affected

FOXL2 (HGNC:1092): (forkhead box L2) This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016]

FOXL2 Gene-Disease associations (from GenCC):

blepharophimosis, ptosis, and epicanthus inversus syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
premature ovarian failure 3
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

FOXL2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_023067.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 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 75 pathogenic variants in the truncated region.

PS3

PS3 evidence extracted from ClinVar submissions: SCV005417057: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-138946068-G-A is Pathogenic according to our data. Variant chr3-138946068-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023067.4. 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
	FOXL2	NM_023067.4	MANE Select	c.655C>T	p.Gln219*	stop_gained	Exon 1 of 1	NP_075555.1	Q53ZD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL2	ENST00000648323.1	MANE Select	c.655C>T	p.Gln219*	stop_gained	Exon 1 of 1	ENSP00000497217.1	P58012

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1265594

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

622124

African (AFR)

AF:

0.00

AC:

AN:

24180

American (AMR)

AF:

0.00

AC:

AN:

13104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20460

East Asian (EAS)

AF:

0.00

AC:

AN:

28154

South Asian (SAS)

AF:

0.00

AC:

AN:

63272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1028814

Other (OTH)

AF:

0.00

AC:

AN:

52064

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Blepharophimosis, ptosis, and epicanthus inversus syndrome (2)

Blepharophimosis, ptosis, and epicanthus inversus syndrome;C1837008:Premature ovarian failure 3 (1)

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

PhyloP100

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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