1-42191406-C-G

Position:

• chr1-42191406-C-G

Variant summary

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

The NM_014947.5(FOXJ3):​c.1248G>C​(p.Gln416His) 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. 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)
• Consequence: FOXJ3 NM_014947.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.863

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 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=0.233268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXJ3	NM_014947.5	c.1248G>C	p.Gln416His	missense_variant	9/13	ENST00000361346.6	NP_055762.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXJ3	ENST00000361346.6	c.1248G>C	p.Gln416His	missense_variant	9/13	1	NM_014947.5	ENSP00000354620	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Oct 03, 2023

The c.1248G>C (p.Q416H) alteration is located in exon 11 (coding exon 8) of the FOXJ3 gene. This alteration results from a G to C substitution at nucleotide position 1248, causing the glutamine (Q) at amino acid position 416 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T;T;.;T;.
Eigen	Benign	-0.076
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	.;.;.;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	0.46	N;N;N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.77	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Benign	0.38	T;T;T;T;T;D
Polyphen		0.65	P;P;P;D;P;.
Vest4		0.43
MutPred		0.22		Gain of glycosylation at P415 (P = 0.0571);Gain of glycosylation at P415 (P = 0.0571);Gain of glycosylation at P415 (P = 0.0571);.;Gain of glycosylation at P415 (P = 0.0571);.;
MVP		0.79
MPC		0.42
ClinPred		0.47	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.49

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: rs138136512; hg19: chr1-42657077;