17-76140250-G-A

Position:

• chr17-76140250-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_001454.4(FOXJ1):​c.146C>T​(p.Ala49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,316,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000038 (0 hom.)
• Consequence: FOXJ1 NM_001454.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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:44127): (RNF157 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058964223).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXJ1	NM_001454.4	c.146C>T	p.Ala49Val	missense_variant	2/3	ENST00000322957.7	NP_001445.2
FOXJ1	XM_047435666.1	c.146C>T	p.Ala49Val	missense_variant	1/2		XP_047291622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXJ1	ENST00000322957.7	c.146C>T	p.Ala49Val	missense_variant	2/3	1	NM_001454.4	ENSP00000323880	P1
RNF157-AS1	ENST00000662723.1	n.89+1730G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000380 AC: 5 AN: 1316366 Hom.: 0 Cov.: 33 AF XY: 0.00000619 AC XY: 4 AN XY: 645754

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: 0.0000796

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.146C>T (p.A49V) alteration is located in exon 2 (coding exon 1) of the FOXJ1 gene. This alteration results from a C to T substitution at nucleotide position 146, causing the alanine (A) at amino acid position 49 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	0.86	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.51	T
Polyphen		0.013	B
Vest4		0.023
MutPred		0.32		Gain of methylation at K48 (P = 0.0443);
MVP		0.41
MPC		0.34
ClinPred		0.30	T
GERP RS		5.0
Varity_R		0.055
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-74136331;