16-86510604-ACGGCGGCGGCGGCGG-ACGGCGGCGGCGG

Variant names:

• chr16-86510604-ACGG-A
• rs574179816
• NM_001451.3:c.57_59delCGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001451.3(FOXF1):​c.57_59delCGG​(p.Gly20del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,181,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G19G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXF1 NM_001451.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.69
• 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 -2 ACMG points.

• BP6: Variant 16-86510604-ACGG-A is Benign according to our data. Variant chr16-86510604-ACGG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2646946.Status of the report is criteria_provided_single_submitter, 1 stars.

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.57_59delCGG	p.Gly20del	disruptive_inframe_deletion	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.57_59delCGG	p.Gly20del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000262426.4	Q12946

Frequencies

GnomAD3 genomes AF: 0.0000666 AC: 10 AN: 150132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.0251 AC: 556 AN: 22192 AF XY: 0.0252

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0623

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0343

GnomAD4 exome AF: 0.00341 AC: 4025 AN: 1181552 Hom.: 0 AF XY: 0.00415 AC XY: 2391 AN XY: 575520

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

African (AFR) AF: 0.00141 AC: 32 AN: 22768

American (AMR) AF: 0.00983 AC: 107 AN: 10882

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 73 AN: 16072

East Asian (EAS) AF: 0.00302 AC: 80 AN: 26460

South Asian (SAS) AF: 0.0193 AC: 898 AN: 46522

European-Finnish (FIN) AF: 0.00891 AC: 299 AN: 33544

Middle Eastern (MID) AF: 0.00446 AC: 16 AN: 3588

European-Non Finnish (NFE) AF: 0.00241 AC: 2344 AN: 974090

Other (OTH) AF: 0.00370 AC: 176 AN: 47626

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000666 AC: 10 AN: 150132 Hom.: 0 Cov.: 32 AF XY: 0.0000682 AC XY: 5 AN XY: 73276

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

African (AFR) AF: 0.0000244 AC: 1 AN: 40910

American (AMR) AF: 0.0000664 AC: 1 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.000579 AC: 2 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.000295 AC: 3 AN: 10180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67430

Other (OTH) AF: 0.000484 AC: 1 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000166817), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=83/17	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: rs574179816; hg19: chr16-86544210; COSMIC: COSV52285864; COSMIC: COSV52285864;