3-138946518-C-G

Variant names:

• chr3-138946518-C-G
• rs387906920
• NM_023067.4:c.205G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_023067.4(FOXL2):​c.205G>C​(p.Glu69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E69K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_023067.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-138946518-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30507.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXL2	NM_023067.4	c.205G>C	p.Glu69Gln	missense_variant	Exon 1 of 1	ENST00000648323.1	NP_075555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1	c.205G>C	p.Glu69Gln	missense_variant	Exon 1 of 1		NM_023067.4	ENSP00000497217.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D
Eigen	Benign	0.066
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.54	N;N
PhyloP100		2.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	.;N
REVEL	Uncertain	0.51
Sift	Benign	0.21	.;T
Sift4G	Benign	0.61	.;T
Polyphen		0.76	P;P
Vest4		0.18
MutPred		0.31		Gain of MoRF binding (P = 0.0253);Gain of MoRF binding (P = 0.0253);
MVP		0.81
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.61
gMVP		0.79
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs387906920; hg19: chr3-138665360;