3-138945608-G-A

Position:

• chr3-138945608-G-A

Variant summary

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

The NM_023067.4(FOXL2):​c.1115C>T​(p.Ser372Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29

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=0.38262123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXL2	NM_023067.4	c.1115C>T	p.Ser372Leu	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.1115C>T	p.Ser372Leu	missense_variant	1/1		NM_023067.4	ENSP00000497217	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457672 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724950

Gnomad4 AFR exome AF: 0.0000898

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

FOXL2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2023

The FOXL2 c.1115C>T variant is predicted to result in the amino acid substitution p.Ser372Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	.;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.0	.;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.026	.;D
Polyphen		0.92	P;P
Vest4		0.23
MutPred		0.21		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.93
ClinPred		0.85	D
GERP RS		3.7
Varity_R		0.23
gMVP		0.32

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: rs1935937641; hg19: chr3-138664450;