16-86510623-CGGCG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001451.3(FOXF1):c.57_60del(p.Gly20GlufsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXF1 NM_001451.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 85 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-86510623-CGGCG-C is Pathogenic according to our data. Variant chr16-86510623-CGGCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 973755.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXF1	NM_001451.3	c.57_60del	p.Gly20GlufsTer49	frameshift_variant	1/2	ENST00000262426.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXF1	ENST00000262426.6	c.57_60del	p.Gly20GlufsTer49	frameshift_variant	1/2	1	NM_001451.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1246470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 610820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alveolar capillary dysplasia with pulmonary venous misalignment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

-

The patient was diagnosed with a deletion of four base pairs in the FOXF1 gene. The result could be confirmed by Sanger sequencing. The above sequence variant was not detectable in the parents. Therefore, the sequence variant probably originated de novo. FOXF1 (MIM* 601089) encodes for the transcription factor Forkhead-Box-F1 (FOXF1) Heterozygous mutations in FOXF1 are associated with the clinical picture of congenital alveolar capillary dysplasia (ACDMPV, MIM #265380). Newborns present with severe respiratory insufficiency with therapy-refractory persistent pulmonary hypertension due to an altered air-blood barrier in the alveoli. Histologically there is a drastic reduction of the capillaries. Sequence variant c.57_60del leads to a shift in the reading frame and thus very probably to premature termination of protein biosynthesis. The variant is not listed in the population database gnomAD. To our knowledge the sequence variant has not been described as the cause of alveolar capillary dysplasia. Similar functional loss mutations have already been described as causative (Szafranski et al. 2016; Bourque et al. 2019; HGMD). According to current knowledge, this is a pathogenic sequence variant (class V). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1969545531; hg19: chr16-86544229;