14-89412458-G-A

Variant summary

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

The NM_005197.4(FOXN3):c.19C>T(p.Pro7Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXN3 NM_005197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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.19C>T	p.Pro7Ser	missense_variant	2/6	ENST00000557258.6
FOXN3	NM_001085471.2	c.19C>T	p.Pro7Ser	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN3	ENST00000557258.6	c.19C>T	p.Pro7Ser	missense_variant	2/6	1	NM_005197.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Feb 10, 2022

The c.19C>T (p.P7S) alteration is located in exon 2 (coding exon 1) of the FOXN3 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the proline (P) at amino acid position 7 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;.;.;.;T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.2	D;D;D;.;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;.;.
Polyphen		0.35	B;B;B;B;B;.;.;.
Vest4		0.34
MutPred		0.27		Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);Gain of phosphorylation at P7 (P = 0.0083);
MVP		0.78
MPC		0.60
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.58

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: rs777712129; hg19: chr14-89878802; COSMIC: COSV99726650; COSMIC: COSV99726650;