3-138946187-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_023067.4(FOXL2):c.536C>G(p.Ala179Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,488,784 control chromosomes in the GnomAD database, including 5,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2760 hom., cov: 33)

Exomes 𝑓: 0.033 ( 2871 hom. )

Consequence

FOXL2
NM_023067.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.759

Publications

15 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, Labcorp Genetics (formerly Invitae), G2P
premature ovarian failure 3
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

FOXL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: -0.80149 (below the threshold of 3.09). GenCC associations: The gene is linked to blepharophimosis, ptosis, and epicanthus inversus syndrome, premature ovarian failure 3.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034596026).

BP6

Variant 3-138946187-G-C is Benign according to our data. Variant chr3-138946187-G-C is described in ClinVar as Benign. ClinVar VariationId is 261662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXL2	NM_023067.4 link	c.536C>G	p.Ala179Gly	missense_variant	Exon 1 of 1	ENST00000648323.1	NP_075555.1	P58012Q53ZD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1 link	c.536C>G	p.Ala179Gly	missense_variant	Exon 1 of 1		NM_023067.4	ENSP00000497217.1		P58012

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18681

AN:

151600

Hom.:

2748

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0547

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.0301

Gnomad SAS

AF:

0.0859

Gnomad FIN

AF:

0.0627

Gnomad MID

AF:

0.0625

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0957

GnomAD2 exomes

AF:

0.0458

AC:

4117

AN:

89912

AF XY:

0.0492

show subpopulations

Gnomad AFR exome

AF:

0.412

Gnomad AMR exome

AF:

0.0262

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.0576

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0445

GnomAD4 exome

AF:

0.0329

AC:

44026

AN:

1337072

Hom.:

2871

Cov.:

AF XY:

0.0341

AC XY:

22516

AN XY:

659490

show subpopulations

African (AFR)

AF:

0.378

AC:

10093

AN:

26686

American (AMR)

AF:

0.0315

AC:

847

AN:

26882

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

556

AN:

23446

East Asian (EAS)

AF:

0.0754

AC:

2269

AN:

30104

South Asian (SAS)

AF:

0.0878

AC:

6478

AN:

73760

European-Finnish (FIN)

AF:

0.0522

AC:

1996

AN:

38262

Middle Eastern (MID)

AF:

0.0755

AC:

334

AN:

4426

European-Non Finnish (NFE)

AF:

0.0177

AC:

18775

AN:

1058130

Other (OTH)

AF:

0.0484

AC:

2678

AN:

55376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2264

4529

6793

9058

11322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.124

AC:

18749

AN:

151712

Hom.:

2760

Cov.:

AF XY:

0.122

AC XY:

9052

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.359

AC:

14873

AN:

41424

American (AMR)

AF:

0.0545

AC:

833

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3470

East Asian (EAS)

AF:

0.0302

AC:

152

AN:

5032

South Asian (SAS)

AF:

0.0858

AC:

413

AN:

4816

European-Finnish (FIN)

AF:

0.0627

AC:

661

AN:

10540

Middle Eastern (MID)

AF:

0.0664

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0215

AC:

1456

AN:

67858

Other (OTH)

AF:

0.102

AC:

214

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

668

1335

2003

2670

3338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.0224

Hom.:

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0158

AC:

ExAC

AF:

0.0496

AC:

1527

Asia WGS

AF:

0.0830

AC:

289

AN:

3456

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 14, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Blepharophimosis, ptosis, and epicanthus inversus syndrome

Benign:1

Nov 03, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.48

.;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N

PhyloP100

0.76

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.43

.;N

REVEL

Benign

0.22

Sift

Benign

0.25

.;T

Sift4G

Benign

0.34

.;T

Polyphen

0.83

P;P

Vest4

0.041

ClinPred

0.014

GERP RS

4.0

Varity_R

0.19

gMVP

0.31

Mutation Taster

=95/5

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over