chr3-138946024-G-GGCTGCAGCCGCAGCT

Variant names:

• chr3-138946024-G-GGCTGCAGCCGCAGCT
• rs387906322
• NM_023067.4:c.684_698dupAGCTGCGGCTGCAGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP3

The NM_023067.4(FOXL2):​c.684_698dupAGCTGCGGCTGCAGC​(p.Ala229_Ala233dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000242 in 1,237,130 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: FOXL2 NM_023067.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.30
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• premature ovarian failure 3

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 3-138946024-G-GGCTGCAGCCGCAGCT is Pathogenic according to our data. Variant chr3-138946024-G-GGCTGCAGCCGCAGCT is described in ClinVar as Pathogenic. ClinVar VariationId is 4870.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP3: Nonframeshift variant in repetitive region in NM_023067.4

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL2	NM_023067.4	MANE Select	c.684_698dupAGCTGCGGCTGCAGC	p.Ala229_Ala233dup	disruptive_inframe_insertion	Exon 1 of 1	NP_075555.1	Q53ZD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL2	ENST00000648323.1	MANE Select	c.684_698dupAGCTGCGGCTGCAGC	p.Ala229_Ala233dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000497217.1	P58012

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1237130 Hom.: 0 Cov.: 31 AF XY: 0.00000330 AC XY: 2 AN XY: 606128

African (AFR) AF: 0.00 AC: 0 AN: 23788

American (AMR) AF: 0.00 AC: 0 AN: 10292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18246

East Asian (EAS) AF: 0.00 AC: 0 AN: 27966

South Asian (SAS) AF: 0.00 AC: 0 AN: 56498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3524

European-Non Finnish (NFE) AF: 0.00000197 AC: 2 AN: 1016066

Other (OTH) AF: 0.0000197 AC: 1 AN: 50838

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=75/25	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906322; hg19: chr3-138664866;