3-138945749-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_023067.4(FOXL2):​c.974C>T​(p.Ala325Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000926 in 1,080,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A325G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.27517262).

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>T	p.Ala325Val	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>T	p.Ala325Val	missense	Exon 1 of 1	ENSP00000497217.1	P58012

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1080204 Hom.: 0 Cov.: 30 AF XY: 0.00000195 AC XY: 1 AN XY: 513232

⚠️ 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: 22634

American (AMR) AF: 0.00 AC: 0 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: 0.00000110 AC: 1 AN: 909752

Other (OTH) AF: 0.00 AC: 0 AN: 42262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.096	T
Polyphen		0.75	P
Vest4		0.13
MutPred		0.13		Loss of glycosylation at P324 (P = 0.0863)
MVP		0.85
ClinPred		0.72	D
GERP RS		3.5
Varity_R		0.16
gMVP		0.27
Mutation Taster		=79/21	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;