rs121908358

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_023067.4(FOXL2):​c.295C>T​(p.Gln99*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 (★).

Frequency

Genomes: not found (cov: 33)

Consequence

FOXL2
NM_023067.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.36
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-138946428-G-A is Pathogenic according to our data. Variant chr3-138946428-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4864.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXL2NM_023067.4 linkuse as main transcriptc.295C>T p.Gln99* stop_gained 1/1 ENST00000648323.1 NP_075555.1 P58012Q53ZD3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXL2ENST00000648323.1 linkuse as main transcriptc.295C>T p.Gln99* stop_gained 1/1 NM_023067.4 ENSP00000497217.1 P58012

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 26, 2024Nonsense variant predicted to result in protein truncation, as the last 278 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.532C>T p.(Q98*); This variant is associated with the following publications: (PMID: 12630957) -
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
43
DANN
Uncertain
1.0
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.87
GERP RS
3.2

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908358; hg19: chr3-138665270; API