rs797044527

Positions:

• chr3-138946073-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_023067.4(FOXL2):​c.650C>T​(p.Ser217Phe) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S217C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.42

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 3-138946073-G-A is Pathogenic according to our data. Variant chr3-138946073-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 180594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXL2	NM_023067.4	c.650C>T	p.Ser217Phe	missense_variant	1/1	ENST00000648323.1	NP_075555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1	c.650C>T	p.Ser217Phe	missense_variant	1/1		NM_023067.4	ENSP00000497217	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1268470 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 623726

Gnomad4 AFR exome AF: 0.00

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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser217 amino acid residue in FOXL2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17277738, 19515849, 22312189). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FOXL2 function (PMID: 18372316, 19010791). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 180594). This missense change has been observed in individual(s) with blepharophimosis (PMID: 11468277, 31077882). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 217 of the FOXL2 protein (p.Ser217Phe). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2023	Published functional studies demonstrate a damaging effect, showing an increased transactivation activity (PMID: 19010791, 19515849, 18372316); Identified in multiple unrelated individuals with features of blepharophimosis-ptosis-epicanthus inversus syndrome referred for genetic testing at GeneDx and in the published literature (PMID: 11468277); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19515849, 18372316, 22312189, 20067892, 19010791, 11468277) -

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

Likely pathogenic, no assertion criteria provided	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Jan 01, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.5	.;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	.;D
Sift4G	Benign	0.40	.;T
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.87		Loss of glycosylation at S217 (P = 0.0013);Loss of glycosylation at S217 (P = 0.0013);
MVP		0.95
ClinPred		0.97	D
GERP RS		3.7
Varity_R		0.39
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044527; hg19: chr3-138664915; COSMIC: COSV57726034; COSMIC: COSV57726034;