rs672601359

Variant names:

• chr3-138945863-G-GGAGGCGGGGGTGCGGCC
• rs672601359
• NM_023067.4:c.843_859dupGGCCGCACCCCCGCCTC

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.843_859dupGGCCGCACCCCCGCCTC​(p.Pro287ArgfsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,091,586 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FOXL2 NM_023067.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 1.98
• Publications: 11 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 33 pathogenic variants in the truncated region.
• PP5: Variant 3-138945863-G-GGAGGCGGGGGTGCGGCC is Pathogenic according to our data. Variant chr3-138945863-G-GGAGGCGGGGGTGCGGCC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162045.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.843_859dupGGCCGCACCCCCGCCTC	p.Pro287ArgfsTer75	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.843_859dupGGCCGCACCCCCGCCTC	p.Pro287ArgfsTer75	frameshift	Exon 1 of 1	ENSP00000497217.1	P58012

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1091586 Hom.: 0 Cov.: 31 AF XY: 0.00000193 AC XY: 1 AN XY: 517384

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22782

American (AMR) AF: 0.00 AC: 0 AN: 8602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14214

East Asian (EAS) AF: 0.00 AC: 0 AN: 26214

South Asian (SAS) AF: 0.00 AC: 0 AN: 22252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2958

European-Non Finnish (NFE) AF: 0.00000431 AC: 4 AN: 928620

Other (OTH) AF: 0.00 AC: 0 AN: 44070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Blepharophimosis, ptosis, and epicanthus inversus syndrome (13)
4	-	-	not provided (4)
1	-	-	FOXL2-related disorder (1)
1	-	-	Premature ovarian failure 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs672601359; hg19: chr3-138664705;