3-138945656-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_023067.4(FOXL2):c.1067T>C(p.Met356Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXL2 NM_023067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXL2	NM_023067.4	c.1067T>C	p.Met356Thr	missense_variant	1/1	ENST00000648323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXL2	ENST00000648323.1	c.1067T>C	p.Met356Thr	missense_variant	1/1		NM_023067.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.1067T>C (p.M356T) alteration is located in exon 1 (coding exon 1) of the FOXL2 gene. This alteration results from a T to C substitution at nucleotide position 1067, causing the methionine (M) at amino acid position 356 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Benign	0.95
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.98	D
Polyphen		0.90	P;P
Vest4		0.59
MutPred		0.37		Loss of catalytic residue at M356 (P = 0.0112);Loss of catalytic residue at M356 (P = 0.0112);
MVP		0.90
ClinPred		0.79	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-138664498;