3-138945851-TGGGGGTGCGGCGGAGGC-TGGGGGTGCGGCGGAGGCGGGGGTGCGGCGGAGGC

Variant names:

• chr3-138945851-T-TGGGGGTGCGGCGGAGGC
• rs797044532
• NM_023067.4:c.855_871dupGCCTCCGCCGCACCCCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_023067.4(FOXL2):​c.855_871dupGCCTCCGCCGCACCCCC​(p.His291ArgfsTer71) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXL2 NM_023067.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 6.77
• Publications: 10 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: Pathogenic. The variant received 16 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 29 pathogenic variants in the truncated region.
• PP5: Variant 3-138945851-T-TGGGGGTGCGGCGGAGGC is Pathogenic according to our data. Variant chr3-138945851-T-TGGGGGTGCGGCGGAGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 4866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL2	NM_023067.4	MANE Select	c.855_871dupGCCTCCGCCGCACCCCC	p.His291ArgfsTer71	frameshift	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.855_871dupGCCTCCGCCGCACCCCC	p.His291ArgfsTer71	frameshift	Exon 1 of 1	ENSP00000497217.1	P58012

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000277 AC: 3 AN: 1082280 Hom.: 0 Cov.: 30 AF XY: 0.00000195 AC XY: 1 AN XY: 512576

African (AFR) AF: 0.0000443 AC: 1 AN: 22548

American (AMR) AF: 0.00 AC: 0 AN: 8206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14006

East Asian (EAS) AF: 0.00 AC: 0 AN: 25864

South Asian (SAS) AF: 0.00 AC: 0 AN: 21458

European-Finnish (FIN) AF: 0.0000463 AC: 1 AN: 21578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2924

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 922102

Other (OTH) AF: 0.00 AC: 0 AN: 43594

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Blepharophimosis, ptosis, and epicanthus inversus syndrome (5)
2	-	-	not provided (2)
1	-	-	BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs797044532; hg19: chr3-138664693;