16-86579309-C-G

Variant names:

• chr16-86579309-C-G
• rs924397043
• NM_005250.3:c.586C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005250.3(FOXL1):​c.586C>G​(p.Leu196Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. L196F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXL1 NM_005250.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.545
• Publications: 0 publications found

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]

FOXL1 Gene-Disease associations (from GenCC):

• otosclerosis 11

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000261161 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13812184).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005250.3. 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
	FOXL1	NM_005250.3	MANE Select	c.586C>G	p.Leu196Val	missense	Exon 1 of 1	NP_005241.1	Q12952

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXL1	ENST00000320241.5	TSL:6 MANE Select	c.586C>G	p.Leu196Val	missense	Exon 1 of 1	ENSP00000326272.3	Q12952
	FOXL1	ENST00000954000.1		c.586C>G	p.Leu196Val	missense	Exon 2 of 2	ENSP00000624059.1
	ENSG00000261161	ENST00000808928.1		n.120+6121C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	3.1
DANN	Benign	0.61
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.55
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.21
Sift	Benign	0.54	T
Sift4G	Benign	0.46	T
Polyphen		0.0010	B
Vest4		0.059
MutPred		0.26		Loss of glycosylation at P195 (P = 0.0989)
MVP		0.80
ClinPred		0.077	T
GERP RS		2.8
Varity_R		0.073
gMVP		0.23

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: rs924397043; hg19: chr16-86612915;