3-138945770-G-T

Position:

• chr3-138945770-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023067.4(FOXL2):​c.953C>A​(p.Pro318Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.988

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2850351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXL2	NM_023067.4	c.953C>A	p.Pro318Gln	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.953C>A	p.Pro318Gln	missense_variant	1/1		NM_023067.4	ENSP00000497217.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duane retraction syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Mar 13, 2024

The heterozygous p.Pro318Gln variant in FOXL2 was identified by our study in one individual with Duane retraction syndrome, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Pro318Gln variant in FOXL2 has not been previously reported in individuals with blepharophimosis, ptosis, and epicanthus inversus syndrome. This variant was absent from large population studies. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Pro318Gln variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.0054	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.44	.;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.17	.;N
REVEL	Benign	0.23
Sift	Benign	0.21	.;T
Sift4G	Benign	0.47	.;T
Polyphen		0.99	D;D
Vest4		0.20
MutPred		0.21		Loss of glycosylation at P318 (P = 0.0143);Loss of glycosylation at P318 (P = 0.0143);
MVP		0.84
ClinPred		0.21	T
GERP RS		3.0
Varity_R		0.084
gMVP		0.29

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: rs1935946242; hg19: chr3-138664612;