1-42188764-T-A

Position:

• chr1-42188764-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014947.5(FOXJ3):​c.1618A>T​(p.Thr540Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXJ3 NM_014947.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.196

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]

ACMG classification

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=0.049405307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXJ3	NM_014947.5	c.1618A>T	p.Thr540Ser	missense_variant	11/13	ENST00000361346.6	NP_055762.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXJ3	ENST00000361346.6	c.1618A>T	p.Thr540Ser	missense_variant	11/13	1	NM_014947.5	ENSP00000354620	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.1618A>T (p.T540S) alteration is located in exon 13 (coding exon 10) of the FOXJ3 gene. This alteration results from a A to T substitution at nucleotide position 1618, causing the threonine (T) at amino acid position 540 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	0.070
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.49
DANN	Benign	0.77
DEOGEN2	Benign	0.0017	T;T;T;T;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T;.;.;.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.049	T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.81	.;L;L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.030	N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.66	T;T;T;T;D;T
Sift4G	Benign	0.73	T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;.;B
Vest4		0.069
MutPred		0.16		.;Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;Gain of relative solvent accessibility (P = 0.0166);
MVP		0.39
MPC		0.23
ClinPred		0.054	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.33

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: rs1312306387; hg19: chr1-42654435;