16-86578821-C-T

Variant names:

• chr16-86578821-C-T
• rs781452561
• NM_005250.3:c.98C>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.98C>T​(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,504 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A33G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: FOXL1 NM_005250.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52
• Publications: 2 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=0.18486336).
• BS2: High AC in GnomAdExome4 at 56 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.98C>T	p.Ala33Val	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.98C>T	p.Ala33Val	missense	Exon 1 of 1	ENSP00000326272.3	Q12952
	FOXL1	ENST00000954000.1		c.98C>T	p.Ala33Val	missense	Exon 2 of 2	ENSP00000624059.1
	FOXL1	ENST00000593625.1	TSL:5	c.98C>T	p.Ala33Val	missense	Exon 2 of 2	ENSP00000472376.1	M0R279

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000482 AC: 12 AN: 248958 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461280 Hom.: 1 Cov.: 30 AF XY: 0.0000481 AC XY: 35 AN XY: 727010

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.46	N
PhyloP100		3.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.31
Sift	Benign	0.27	T
Sift4G	Benign	0.15	T
Polyphen		0.44	B
Vest4		0.12
MutPred		0.41		Loss of disorder (P = 0.0191)
MVP		0.89
ClinPred		0.070	T
GERP RS		4.2
PromoterAI		0.0073	Neutral
Varity_R		0.062
gMVP		0.53
Mutation Taster		=77/23	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: rs781452561; hg19: chr16-86612427; COSMIC: COSV57215520;