14-89412350-A-C

Variant summary

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

The NM_005197.4(FOXN3):c.127T>G(p.Phe43Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXN3 NM_005197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15973648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN3	NM_005197.4	c.127T>G	p.Phe43Val	missense_variant	2/6	ENST00000557258.6
FOXN3	NM_001085471.2	c.127T>G	p.Phe43Val	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN3	ENST00000557258.6	c.127T>G	p.Phe43Val	missense_variant	2/6	1	NM_005197.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

Jun 03, 2022

The c.127T>G (p.F43V) alteration is located in exon 2 (coding exon 1) of the FOXN3 gene. This alteration results from a T to G substitution at nucleotide position 127, causing the phenylalanine (F) at amino acid position 43 to be replaced by a valine (V). 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	0.083
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	20
Dann	Benign	0.91
DEOGEN2	Benign	0.10	T;T;.;.;.;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	1.9	M;M;M;M;M;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.17	N;N;N;.;N;N;N;D
REVEL	Benign	0.28
Sift	Benign	0.31	T;T;T;.;T;T;T;D
Sift4G	Benign	0.67	T;T;T;T;T;T;.;.
Polyphen		0.18	B;B;B;B;B;.;.;.
Vest4		0.32
MutPred		0.19		Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);Loss of glycosylation at S44 (P = 0.2272);
MVP		0.84
MPC		0.48
ClinPred		0.53	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.29

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: rs1891565176; hg19: chr14-89878694;