16-86579234-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005250.3(FOXL1):c.511G>A(p.Glu171Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 33)
• Consequence: FOXL1 NM_005250.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0930

Genes affected

FOXL1 (HGNC:3817): (forkhead box L1) This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors are characterized by a distinct DNA-binding forkhead domain and play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14293543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXL1	NM_005250.3	c.511G>A	p.Glu171Lys	missense_variant	1/1	ENST00000320241.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXL1	ENST00000320241.5	c.511G>A	p.Glu171Lys	missense_variant	1/1		NM_005250.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151966 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151966 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74226

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The c.511G>A (p.E171K) alteration is located in exon 1 (coding exon 1) of the FOXL1 gene. This alteration results from a G to A substitution at nucleotide position 511, causing the glutamic acid (E) at amino acid position 171 to be replaced by a lysine (K). 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	Benign	0.077
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	7.9
Dann	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.20
Sift	Benign	0.15	T
Sift4G	Benign	0.67	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.38		Gain of ubiquitination at E171 (P = 0.0011);
MVP		0.72
ClinPred		0.13	T
GERP RS		1.4
Varity_R		0.048
gMVP		0.34

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

Other links and lift over

dbSNP: rs1437058351; hg19: chr16-86612840;