16-86510604-A-ACGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001451.3(FOXF1):c.57_59dup(p.Gly22dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,379,102 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: FOXF1 NM_001451.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.451

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 16-86510604-A-ACGG is Benign according to our data. Variant chr16-86510604-A-ACGG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 320786.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 253 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXF1	NM_001451.3	c.57_59dup	p.Gly22dup	inframe_insertion	1/2	ENST00000262426.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXF1	ENST00000262426.6	c.57_59dup	p.Gly22dup	inframe_insertion	1/2	1	NM_001451.3	P1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 253 AN: 150202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000663

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00691

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00194

GnomAD3 exomes AF: 0.000811 AC: 18 AN: 22192 Hom.: 0 AF XY: 0.000681 AC XY: 9 AN XY: 13220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000597

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00170 AC: 2093 AN: 1228792 Hom.: 2 Cov.: 34 AF XY: 0.00182 AC XY: 1095 AN XY: 600736

Gnomad4 AFR exome AF: 0.000504

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00800

Gnomad4 EAS exome AF: 0.00375

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.000940

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00246

GnomAD4 genome AF: 0.00168 AC: 253 AN: 150310 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 109 AN XY: 73432

Gnomad4 AFR AF: 0.000171

Gnomad4 AMR AF: 0.000663

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00694

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00137

Gnomad4 NFE AF: 0.00211

Gnomad4 OTH AF: 0.00191

Bravo AF: 0.00151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This variant, c.57_59dup, results in the insertion of 1 amino acid(s) of the FOXF1 protein (p.Gly23dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FOXF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 320786). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FOXF1: BS1, BS2 -

Alveolar capillary dysplasia with pulmonary venous misalignment Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

FOXF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs574179816; hg19: chr16-86544210;