dbSNP rs797044528: FOXL2:p.Gly269AlafsTer2 (chr3-138945918-CG-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_023067.4(FOXL2):c.804delC(p.Gly269AlafsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXL2
NM_023067.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.636

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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 26 pathogenic variants in the truncated region.

PP5

Variant 3-138945918-CG-C is Pathogenic according to our data. Variant chr3-138945918-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 369930.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXL2	NM_023067.4 link	c.804delC	p.Gly269AlafsTer2	frameshift_variant	Exon 1 of 1	ENST00000648323.1	NP_075555.1	P58012Q53ZD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXL2	ENST00000648323.1 link	c.804delC	p.Gly269AlafsTer2	frameshift_variant	Exon 1 of 1		NM_023067.4	ENSP00000497217.1		P58012

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150810

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000834

AC:

AN:

59924

AF XY:

0.000115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000363

Gnomad NFE exome

AF:

0.0000867

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000338

AC:

AN:

1184666

Hom.:

Cov.:

AF XY:

0.00000525

AC XY:

AN XY:

571578

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

24564

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

15350

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

16018

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

29164

Gnomad4 SAS exome

AF:

0.0000545

AC:

AN:

36680

Gnomad4 FIN exome

AF:

0.0000375

AC:

AN:

26668

Gnomad4 NFE exome

AF:

0.00000102

AC:

AN:

984590

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

48250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

150810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73604

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Blepharophimosis, ptosis, and epicanthus inversus syndrome

Pathogenic:2

Nov 03, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2015

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=7/193

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over