NM_005250.3:c.586C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005250.3(FOXL1):​c.586C>T​(p.Leu196Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,457,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: FOXL1 NM_005250.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15870285).
• BS2: High AC in GnomAdExome4 at 59 AD gene.

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>T	p.Leu196Phe	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>T	p.Leu196Phe	missense	Exon 1 of 1	ENSP00000326272.3	Q12952
	FOXL1	ENST00000954000.1		c.586C>T	p.Leu196Phe	missense	Exon 2 of 2	ENSP00000624059.1
	ENSG00000261161	ENST00000808928.1		n.120+6121C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151924 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 59 AN: 1305504 Hom.: 0 Cov.: 36 AF XY: 0.0000435 AC XY: 28 AN XY: 643702

African (AFR) AF: 0.00 AC: 0 AN: 25634

American (AMR) AF: 0.00 AC: 0 AN: 23460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21746

East Asian (EAS) AF: 0.00 AC: 0 AN: 29392

South Asian (SAS) AF: 0.00 AC: 0 AN: 69366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.0000565 AC: 59 AN: 1044244

Other (OTH) AF: 0.00 AC: 0 AN: 53852

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151924 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74208

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.0
DANN	Benign	0.90
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.55
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.16
Sift	Benign	0.70	T
Sift4G	Benign	0.31	T
Polyphen		0.12	B
Vest4		0.068
MutPred		0.29		Gain of glycosylation at P193 (P = 0.2401)
MVP		0.88
ClinPred		0.14	T
GERP RS		2.8
Varity_R		0.066
gMVP		0.19
Mutation Taster		=96/4	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: rs924397043; hg19: chr16-86612915;