17-76139993-G-C

Position:

• chr17-76139993-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001454.4(FOXJ1):​c.403C>G​(p.Gln135Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FOXJ1 NM_001454.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20128673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXJ1	NM_001454.4	c.403C>G	p.Gln135Glu	missense_variant	2/3	ENST00000322957.7	NP_001445.2
FOXJ1	XM_047435666.1	c.403C>G	p.Gln135Glu	missense_variant	1/2		XP_047291622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXJ1	ENST00000322957.7	c.403C>G	p.Gln135Glu	missense_variant	2/3	1	NM_001454.4	ENSP00000323880.4
RNF157-AS1	ENST00000662723.1	n.89+1473G>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461456 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ciliary dyskinesia, primary, 43 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Oct 10, 2022

The FOXJ1 c.403C>G variant is classified as VUS (PM2) The FOXJ1 c.403C>G variant is a single nucleotide change in exon 2/3 of the FOXJ1 gene, which is predicted to change the amino acid glutamine at position 135 in the protein to glutamic acid. This variant is absent from population databases (PM2). There are mixed computational predictions (neither PP3 or BP4 applied). This variant has not been reported in dbSNP, ClinVar or HGMD (2022.3). The variant has not been described in the literature to date. Other FOXJ1 variants with a reported loss of function have been described in association with respiratory insufficiency, hydrocephalus and situs inversus (PMID: 31630787, PMID: 34132502, PMID: 33077954) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.022
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.078	D
MutationAssessor	Benign	0.25	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.40
Sift	Benign	0.37	T
Sift4G	Benign	0.47	T
Polyphen		0.011	B
Vest4		0.10
MutPred		0.65		Loss of MoRF binding (P = 0.0784);
MVP		0.73
MPC		0.38
ClinPred		0.69	D
GERP RS		5.3
Varity_R		0.40
gMVP		0.52

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: rs2068504768; hg19: chr17-74136074;