3-138945901-G-C

Variant names:

• chr3-138945901-G-C
• rs104893738
• NM_023067.4:c.822C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_023067.4(FOXL2):​c.822C>G​(p.Tyr274*) 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
• Publications: 3 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: Pathogenic. The variant received 12 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 41 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 VariationId is 4861.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL2	NM_023067.4	MANE Select	c.822C>G	p.Tyr274*	stop_gained	Exon 1 of 1	NP_075555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL2	ENST00000648323.1	MANE Select	c.822C>G	p.Tyr274*	stop_gained	Exon 1 of 1	ENSP00000497217.1

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

African (AFR) AF: 0.00 AC: 0 AN: 24174

American (AMR) AF: 0.00 AC: 0 AN: 13730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15570

East Asian (EAS) AF: 0.00 AC: 0 AN: 28428

South Asian (SAS) AF: 0.00 AC: 0 AN: 33604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 973838

Other (OTH) AF: 0.00 AC: 0 AN: 47404

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

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.0
Vest4		0.85
GERP RS		2.4
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893738; hg19: chr3-138664743;