3-138945749-G-C

Variant names:

• chr3-138945749-G-C
• rs774457946
• NM_023067.4:c.974C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS2_Supporting

The NM_023067.4(FOXL2):​c.974C>G​(p.Ala325Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000976 in 1,229,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• premature ovarian failure 3

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: -0.80149 (below the threshold of 3.09). GenCC associations: The gene is linked to blepharophimosis, ptosis, and epicanthus inversus syndrome, premature ovarian failure 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23060292).
• BS2: High AC in GnomAd4 at 8 AD,Unknown gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.974C>G	p.Ala325Gly	missense	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.974C>G	p.Ala325Gly	missense	Exon 1 of 1	ENSP00000497217.1	P58012

Frequencies

GnomAD3 genomes AF: 0.0000537 AC: 8 AN: 149064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000195

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: 0.00 AC: 0 AN: 25156 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000370 AC: 4 AN: 1080204 Hom.: 0 Cov.: 30 AF XY: 0.00000390 AC XY: 2 AN XY: 513232

African (AFR) AF: 0.0000442 AC: 1 AN: 22634

American (AMR) AF: 0.000194 AC: 2 AN: 10288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13958

East Asian (EAS) AF: 0.00 AC: 0 AN: 24754

South Asian (SAS) AF: 0.00 AC: 0 AN: 24380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 909752

Other (OTH) AF: 0.0000237 AC: 1 AN: 42262

GnomAD4 genome AF: 0.0000536 AC: 8 AN: 149174 Hom.: 0 Cov.: 33 AF XY: 0.0000550 AC XY: 4 AN XY: 72742

African (AFR) AF: 0.000194 AC: 8 AN: 41158

American (AMR) AF: 0.00 AC: 0 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67000

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000183 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.20	T
Polyphen		0.56	P
Vest4		0.087
MutPred		0.11		Gain of relative solvent accessibility (P = 0.005)
MVP		0.81
ClinPred		0.21	T
GERP RS		3.5
Varity_R		0.24
gMVP		0.26
Mutation Taster		=81/19	polymorphism

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: rs774457946; hg19: chr3-138664591;