3-138945918-C-CG

Position:

• chr3-138945918-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_023067.4(FOXL2):​c.804_805insC​(p.Gly269ArgfsTer265) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000844 in 1,184,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: FOXL2 NM_023067.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 0.636

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 Pathogenic. Variant got 18 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 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-138945918-C-CG is Pathogenic according to our data. Variant chr3-138945918-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 4858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXL2	NM_023067.4	c.804_805insC	p.Gly269ArgfsTer265	frameshift_variant	1/1	ENST00000648323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXL2	ENST00000648323.1	c.804_805insC	p.Gly269ArgfsTer265	frameshift_variant	1/1		NM_023067.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.44e-7 AC: 1 AN: 1184694 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 571600

Gnomad4 AFR exome AF: 0.0000407

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blepharophimosis, ptosis, and epicanthus inversus syndrome Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 03, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2023	This sequence change creates a premature translational stop signal (p.Gly269Argfs*265) in the FOXL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the FOXL2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with blepharophimosis (PMID: 17277738). ClinVar contains an entry for this variant (Variation ID: 4858). This variant disrupts a region of the FOXL2 protein in which other variant(s) (p.Ala304Hisfs*52) have been determined to be pathogenic (PMID: 11468277). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2024

The c.804dupC (p.G269Rfs*265) alteration, located in exon 1 (coding exon 1) of the FOXL2 gene, consists of a duplication of C at position 804, causing a translational frameshift with a predicted alternate stop codon after 265 amino acids. Frameshifts are typically deleterious in nature; however, because FOXL2 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and an altered protein could still be expressed. This frameshift impacts the last 29% of the native protein and results in the elongation of the protein by 157 amino acids. The exact functional impact of these altered amino acids is unknown at this time. The FOXL2 c.804dupC alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), some of which also had a family history of BPES, and this variant was shown to segregate with disease in one family (Wang, 2007; Kaur, 2011; Bunyan, 2019). Additionally, this variant was detected de novo in one female with premature ovarian insufficiency, narrow palpebral fissures, and polycystic ovary morphology (Shen, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

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: rs797044528; hg19: chr3-138664760;