14-89162530-T-A

Variant summary

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

The NM_005197.4(FOXN3):c.1291A>T(p.Met431Leu) variant causes a missense change. 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: 31)
• Consequence: FOXN3 NM_005197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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=0.15125722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN3	NM_005197.4	c.1291A>T	p.Met431Leu	missense_variant	6/6	ENST00000557258.6
FOXN3	NM_001085471.2	c.1357A>T	p.Met453Leu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN3	ENST00000557258.6	c.1291A>T	p.Met431Leu	missense_variant	6/6	1	NM_005197.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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, 2022

The c.1357A>T (p.M453L) alteration is located in exon 7 (coding exon 6) of the FOXN3 gene. This alteration results from a A to T substitution at nucleotide position 1357, causing the methionine (M) at amino acid position 453 to be replaced by a leucine (L). 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	0.58
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	18
Dann	Benign	0.46
DEOGEN2	Benign	0.085	T;T;.;.;.
Eigen	Benign	-0.017
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.81	N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.090	N;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0060	B;B;P;P;P
Vest4		0.34
MutPred		0.30		Gain of methylation at K454 (P = 0.0338);Gain of methylation at K454 (P = 0.0338);.;.;.;
MVP		0.71
MPC		0.34
ClinPred		0.33	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.31

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: chr14-89628874;