3-138945901-G-C

Position:

• chr3-138945901-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_023067.4(FOXL2):​c.822C>G​(p.Tyr274Ter) variant causes a stop gained change involving the alteration of a non-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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXL2 NM_023067.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.02

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 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. Fraction of 0.273 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-138945901-G-C is Pathogenic according to our data. Variant chr3-138945901-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4861.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXL2	NM_023067.4	c.822C>G	p.Tyr274Ter	stop_gained	1/1	ENST00000648323.1	NP_075555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1	c.822C>G	p.Tyr274Ter	stop_gained	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: 1165492 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 560238

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

Revision: criteria provided, single submitter

Submissions by phenotype

Blepharophimosis, ptosis, and epicanthus inversus syndrome;C1837008:Premature ovarian failure 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A
Vest4		0.85
GERP RS		2.4

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: rs104893738; hg19: chr3-138664743;