14-89350743-C-A

Position:

• chr14-89350743-C-A

Variant summary

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

The NM_005197.4(FOXN3):​c.609G>T​(p.Leu203Phe) 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 NM_005197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05

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]

FOXN3 (HGNC:):

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	Protein	UniProt
FOXN3	NM_005197.4	c.609G>T	p.Leu203Phe	missense_variant	3/6	ENST00000557258.6	NP_005188.2
FOXN3	NM_001085471.2	c.609G>T	p.Leu203Phe	missense_variant	3/7		NP_001078940.1
LOC101928817	NR_188029.1	n.207+250C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXN3	ENST00000557258.6	c.609G>T	p.Leu203Phe	missense_variant	3/6	1	NM_005197.4	ENSP00000452005.1

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

Apr 20, 2024

The c.609G>T (p.L203F) alteration is located in exon 3 (coding exon 2) of the FOXN3 gene. This alteration results from a G to T substitution at nucleotide position 609, causing the leucine (L) at amino acid position 203 to be replaced by a phenylalanine (F). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T;.;.;.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D;.;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D;D;D;.;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;.;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.
Vest4		0.50
MutPred		0.49		Loss of stability (P = 0.0732);Loss of stability (P = 0.0732);Loss of stability (P = 0.0732);Loss of stability (P = 0.0732);Loss of stability (P = 0.0732);.;Loss of stability (P = 0.0732);
MVP		0.75
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.75
gMVP		0.54

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: chr14-89817087;