17-76140172-A-AG

Position:

• chr17-76140172-A-AG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001454.4(FOXJ1):​c.223dupC​(p.Leu75fs) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXJ1 NM_001454.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.43

Genes affected

FOXJ1 (HGNC:3816): (forkhead box J1) This gene encodes a member of the forkhead family of transcription factors. Similar genes in zebrafish and mouse have been shown to regulate the transcription of genes that control the production of motile cilia. The mouse ortholog also functions in the determination of left-right asymmetry. Polymorphisms in this gene are associated with systemic lupus erythematosus and allergic rhinitis.[provided by RefSeq, Sep 2009]

RNF157-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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. Fraction of 0.824 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-76140172-A-AG is Pathogenic according to our data. Variant chr17-76140172-A-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3390985.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXJ1	NM_001454.4	c.223dupC	p.Leu75fs	frameshift_variant	2/3	ENST00000322957.7	NP_001445.2
FOXJ1	XM_047435666.1	c.223dupC	p.Leu75fs	frameshift_variant	1/2		XP_047291622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXJ1	ENST00000322957.7	c.223dupC	p.Leu75fs	frameshift_variant	2/3	1	NM_001454.4	ENSP00000323880.4
RNF157-AS1	ENST00000662723.1	n.89+1658dupG		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ciliary dyskinesia, primary, 43 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Aug 26, 2024

The variant results in a frameshift at protein position 75 and the formation of a premature stop codon after 124 amino acids. According to predictions, the modified gene product is not degraded by nonsense-mediated decay. However, the modification affects the DNA-binding forkhead domain of FOXJ1, which is critical for the protein function. The disease associated with this gene is highly consistent with the patient's reported phenotype. The variant has not yet been described in ClinVar. This variant is classified as very rare since it is absent in gnomAD v4.1.0. In summary, the variant is classified as likely pathogenic. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-74136253;