chr16-86510600-C-T

Variant names:

• chr16-86510600-C-T
• rs758526963
• NM_001451.3:c.31C>T

Variant summary

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

The NM_001451.3(FOXF1):​c.31C>T​(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,390,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: FOXF1 NM_001451.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0490
• Publications: 0 publications found

Genes affected

FOXF1 (HGNC:3809): (forkhead box F1) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the regulation of pulmonary genes as well as embryonic development. [provided by RefSeq, Jul 2008]

FOXF1 Gene-Disease associations (from GenCC):

• alveolar capillary dysplasia with misalignment of pulmonary veins

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19417882).
• BS2: High AC in GnomAd4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001451.3. 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
	FOXF1	NM_001451.3	MANE Select	c.31C>T	p.Pro11Ser	missense	Exon 1 of 2	NP_001442.2	Q12946

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXF1	ENST00000262426.6	TSL:1 MANE Select	c.31C>T	p.Pro11Ser	missense	Exon 1 of 2	ENSP00000262426.4	Q12946

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151614 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000612 AC: 2 AN: 32702 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.0000234 AC: 29 AN: 1238294 Hom.: 0 Cov.: 33 AF XY: 0.0000264 AC XY: 16 AN XY: 606242

African (AFR) AF: 0.000879 AC: 21 AN: 23878

American (AMR) AF: 0.000246 AC: 3 AN: 12214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17544

East Asian (EAS) AF: 0.00 AC: 0 AN: 28708

South Asian (SAS) AF: 0.00 AC: 0 AN: 51868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3804

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1013304

Other (OTH) AF: 0.0000790 AC: 4 AN: 50616

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151722 Hom.: 0 Cov.: 33 AF XY: 0.000216 AC XY: 16 AN XY: 74190

African (AFR) AF: 0.000724 AC: 30 AN: 41418

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67838

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000219

ExAC AF: 0.0000306 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.049
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.24
Sift	Uncertain	0.018	D
Sift4G	Benign	0.62	T
Polyphen		0.90	P
Vest4		0.11
MutPred		0.18		Gain of phosphorylation at P11 (P = 0.0146)
MVP		0.46
ClinPred		0.037	T
GERP RS		3.5
PromoterAI		0.16	Neutral
Varity_R		0.12
gMVP		0.56
Mutation Taster		=78/22	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: rs758526963; hg19: chr16-86544206;