NM_001451.3:c.16G>T

Variant names:

• chr16-86510585-G-T
• rs922959342
• NM_001451.3:c.16G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001451.3(FOXF1):​c.16G>T​(p.Glu6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000817 in 1,224,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: FOXF1 NM_001451.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 64 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.16G>T	p.Glu6*	stop_gained	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.16G>T	p.Glu6*	stop_gained	Exon 1 of 2	ENSP00000262426.4	Q12946

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.17e-7 AC: 1 AN: 1224564 Hom.: 0 Cov.: 33 AF XY: 0.00000167 AC XY: 1 AN XY: 599746

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23846

American (AMR) AF: 0.00 AC: 0 AN: 13516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18262

East Asian (EAS) AF: 0.00 AC: 0 AN: 27516

South Asian (SAS) AF: 0.00 AC: 0 AN: 50894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3640

European-Non Finnish (NFE) AF: 9.96e-7 AC: 1 AN: 1004036

Other (OTH) AF: 0.00 AC: 0 AN: 49914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.25	N
PhyloP100		2.0
Vest4		0.55
GERP RS		3.5
PromoterAI		0.0068	Neutral
Mutation Taster		=32/168	disease causing (fs/PTC)

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: rs922959342; hg19: chr16-86544191;