14-89190393-G-T

Variant summary

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

The ENST00000345097.8(FOXN3):c.802C>A(p.Gln268Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXN3 ENST00000345097.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

Genes affected

FOXN3 (HGNC:1928): (forkhead box N3) This gene is a member of the forkhead/winged helix transcription factor family. Checkpoints are eukaryotic DNA damage-inducible cell cycle arrests at G1 and G2. Checkpoint suppressor 1 suppresses multiple yeast checkpoint mutations including mec1, rad9, rad53 and dun1 by activating a MEC1-independent checkpoint pathway. Alternative splicing is observed at the locus, resulting in distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN3	NM_005197.4	c.746-9587C>A		intron_variant		ENST00000557258.6
FOXN3	NM_001085471.2	c.802C>A	p.Gln268Lys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN3	ENST00000557258.6	c.746-9587C>A		intron_variant		1	NM_005197.4	A1

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 26, 2022

The c.802C>A (p.Q268K) alteration is located in exon 5 (coding exon 4) of the FOXN3 gene. This alteration results from a C to A substitution at nucleotide position 802, causing the glutamine (Q) at amino acid position 268 to be replaced by a lysine (K). 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	0.091
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.11	T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.20	T;T;D
Sift4G	Benign	0.11	T;T;D
Polyphen		0.083	B;B;.
Vest4		0.53
MutPred		0.40		Gain of ubiquitination at Q268 (P = 0.006);Gain of ubiquitination at Q268 (P = 0.006);.;
MVP		0.91
MPC		0.47
ClinPred		0.74	D
GERP RS		5.7
Varity_R		0.12
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-89656737;