Genetic Variant FOXJ3:p.Ala589Ser (chr1-42179814-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014947.5(FOXJ3):c.1765G>T(p.Ala589Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

FOXJ3
NM_014947.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Variant links:

Genes affected

FOXJ3 (HGNC:29178): (forkhead box J3) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FOXJ3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059868604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXJ3	NM_014947.5 link	c.1765G>T	p.Ala589Ser	missense_variant	Exon 13 of 13	ENST00000361346.6	NP_055762.3	Q9UPW0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXJ3	ENST00000361346.6 link	c.1765G>T	p.Ala589Ser	missense_variant	Exon 13 of 13	1	NM_014947.5	ENSP00000354620.1		Q9UPW0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1765G>T (p.A589S) alteration is located in exon 15 (coding exon 12) of the FOXJ3 gene. This alteration results from a G to T substitution at nucleotide position 1765, causing the alanine (A) at amino acid position 589 to be replaced by a serine (S). 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

0.076

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0085

T;T;T;T;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.92

D;.;.;.;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.060

T;T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.34

.;N;N;N;.;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.29

N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.97

T;T;T;T;T;T

Sift4G

Benign

0.78

T;T;T;T;T;T

Polyphen

0.13

.;B;B;B;.;B

Vest4

0.12

MutPred

0.13

.;Gain of phosphorylation at A589 (P = 0.099);Gain of phosphorylation at A589 (P = 0.099);Gain of phosphorylation at A589 (P = 0.099);.;Gain of phosphorylation at A589 (P = 0.099);

MVP

0.36

MPC

0.24

ClinPred

0.51

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over