3-138946222-G-A

Variant names:

• chr3-138946222-G-A
• rs61750361
• NM_023067.4:c.501C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_023067.4(FOXL2):​c.501C>T​(p.Phe167Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,537,794 control chromosomes in the GnomAD database, including 4,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2227 hom., cov: 33)
  • Exomes 𝑓: 0.033 (2732 hom.)
• Consequence: FOXL2 NM_023067.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0650
• Publications: 9 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-138946222-G-A is Benign according to our data. Variant chr3-138946222-G-A is described in ClinVar as Benign. ClinVar VariationId is 261661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.065 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

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.501C>T	p.Phe167Phe	synonymous	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.501C>T	p.Phe167Phe	synonymous	Exon 1 of 1	ENSP00000497217.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17065 AN: 151604 Hom.: 2215 Cov.: 33

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0853

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.0613

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0924

GnomAD2 exomes AF: 0.0501 AC: 6865 AN: 136944 AF XY: 0.0512

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0429

GnomAD4 exome AF: 0.0329 AC: 45616 AN: 1386086 Hom.: 2732 Cov.: 32 AF XY: 0.0341 AC XY: 23317 AN XY: 684396

African (AFR) AF: 0.342 AC: 10353 AN: 30240

American (AMR) AF: 0.0288 AC: 996 AN: 34610

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 586 AN: 24742

East Asian (EAS) AF: 0.0671 AC: 2312 AN: 34456

South Asian (SAS) AF: 0.0880 AC: 6930 AN: 78712

European-Finnish (FIN) AF: 0.0542 AC: 2383 AN: 43944

Middle Eastern (MID) AF: 0.0750 AC: 369 AN: 4918

European-Non Finnish (NFE) AF: 0.0177 AC: 19021 AN: 1077020

Other (OTH) AF: 0.0464 AC: 2666 AN: 57444

GnomAD4 genome AF: 0.113 AC: 17131 AN: 151708 Hom.: 2227 Cov.: 33 AF XY: 0.112 AC XY: 8316 AN XY: 74164

African (AFR) AF: 0.321 AC: 13307 AN: 41402

American (AMR) AF: 0.0521 AC: 795 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3466

East Asian (EAS) AF: 0.0298 AC: 150 AN: 5038

South Asian (SAS) AF: 0.0852 AC: 410 AN: 4810

European-Finnish (FIN) AF: 0.0627 AC: 662 AN: 10564

Middle Eastern (MID) AF: 0.0660 AC: 19 AN: 288

European-Non Finnish (NFE) AF: 0.0214 AC: 1452 AN: 67848

Other (OTH) AF: 0.0986 AC: 208 AN: 2110

Alfa AF: 0.0589 Hom.: 359

Bravo AF: 0.118

Asia WGS AF: 0.0820 AC: 288 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 14, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Blepharophimosis, ptosis, and epicanthus inversus syndrome Benign:1

Nov 03, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.97
PhyloP100		0.065
Mutation Taster		=100/0	polymorphism (auto)

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: rs61750361; hg19: chr3-138665064;