3-138945652-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_023067.4(FOXL2):c.1071T>C(p.His357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,606,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: FOXL2 NM_023067.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 3-138945652-A-G is Benign according to our data. Variant chr3-138945652-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 435242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-138945652-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.66 with no splicing effect.
• BS2: High AC in GnomAd at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXL2	NM_023067.4	c.1071T>C	p.His357=	synonymous_variant	1/1	ENST00000648323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXL2	ENST00000648323.1	c.1071T>C	p.His357=	synonymous_variant	1/1		NM_023067.4	P1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152018 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000544 AC: 132 AN: 242766 Hom.: 0 AF XY: 0.000557 AC XY: 74 AN XY: 132820

Gnomad AFR exome AF: 0.0000654

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.00364

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000467 AC: 679 AN: 1453988 Hom.: 1 Cov.: 31 AF XY: 0.000473 AC XY: 342 AN XY: 722772

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000584

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.000750

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74368

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000710 Hom.: 0

Bravo AF: 0.000514

EpiCase AF: 0.00120

EpiControl AF: 0.00125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	FOXL2: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 05, 2017

- -

FOXL2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	7.8
Dann	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs146709691; hg19: chr3-138664494;