Genetic Variant FOXL2:c.-251G>A (chr3-138946973-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_023067.4(FOXL2):c.-251G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 561,014 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 415 hom., cov: 32)

Exomes 𝑓: 0.013 ( 499 hom. )

Consequence

FOXL2
NM_023067.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.785

Publications

0 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 links:

FOXL2NB (HGNC:34428): (FOXL2 neighbor) Located in fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

FOXL2NB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 3-138946973-C-T is Benign according to our data. Variant chr3-138946973-C-T is described in ClinVar as Benign. ClinVar VariationId is 261660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXL2	NM_023067.4 link	c.-251G>A		5_prime_UTR_variant	Exon 1 of 1	ENST00000648323.1	NP_075555.1
FOXL2NB	NM_001040061.3 link	c.-392C>T		upstream_gene_variant		ENST00000383165.4	NP_001035150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1 link	c.-251G>A		5_prime_UTR_variant	Exon 1 of 1		NM_023067.4	ENSP00000497217.1
FOXL2NB	ENST00000383165.4 link	c.-392C>T		upstream_gene_variant		2	NM_001040061.3	ENSP00000372651.3

Frequencies

GnomAD3 genomes

AF:

0.0274

AC:

4165

AN:

152104

Hom.:

411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0234

Gnomad SAS

AF:

0.0220

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.0378

GnomAD4 exome

AF:

0.0133

AC:

5453

AN:

408792

Hom.:

499

Cov.:

AF XY:

0.0130

AC XY:

2767

AN XY:

212262

show subpopulations

African (AFR)

AF:

0.0169

AC:

146

AN:

8632

American (AMR)

AF:

0.257

AC:

3223

AN:

12524

Ashkenazi Jewish (ASJ)

AF:

0.0000817

AC:

AN:

12244

East Asian (EAS)

AF:

0.0317

AC:

817

AN:

25810

South Asian (SAS)

AF:

0.0179

AC:

592

AN:

33150

European-Finnish (FIN)

AF:

0.000159

AC:

AN:

37734

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

1826

European-Non Finnish (NFE)

AF:

0.000956

AC:

242

AN:

253138

Other (OTH)

AF:

0.0177

AC:

419

AN:

23734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

223

446

670

893

1116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.0274

AC:

4177

AN:

152222

Hom.:

415

Cov.:

AF XY:

0.0311

AC XY:

2313

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0181

AC:

750

AN:

41532

American (AMR)

AF:

0.199

AC:

3047

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0236

AC:

122

AN:

5162

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4822

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

67994

Other (OTH)

AF:

0.0369

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

174

349

523

698

872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0193

Hom.:

Bravo

AF:

0.0446

Asia WGS

AF:

0.0370

AC:

127

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.79

PromoterAI

-0.0065

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over