14-89162673-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005197.4(FOXN3):​c.1148C>T​(p.Pro383Leu) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Consequence

FOXN3
NM_005197.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.051151335).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXN3NM_005197.4 linkuse as main transcriptc.1148C>T p.Pro383Leu missense_variant 6/6 ENST00000557258.6 NP_005188.2 O00409-2
FOXN3NM_001085471.2 linkuse as main transcriptc.1214C>T p.Pro405Leu missense_variant 7/7 NP_001078940.1 O00409-1A0A024R6I1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXN3ENST00000557258.6 linkuse as main transcriptc.1148C>T p.Pro383Leu missense_variant 6/61 NM_005197.4 ENSP00000452005.1 O00409-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 03, 2024The c.1214C>T (p.P405L) alteration is located in exon 7 (coding exon 6) of the FOXN3 gene. This alteration results from a C to T substitution at nucleotide position 1214, causing the proline (P) at amino acid position 405 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
Benign
0.076
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
19
DANN
Benign
0.95
DEOGEN2
Benign
0.079
T;T;.;.;.
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.86
.;D;.;D;.
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.051
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.41
N;N;.;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.22
N;N;N;.;N
REVEL
Benign
0.057
Sift
Benign
0.28
T;T;T;.;T
Sift4G
Benign
0.38
T;T;T;T;T
Polyphen
0.0
B;B;B;B;B
Vest4
0.041
MutPred
0.17
Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);.;.;.;
MVP
0.34
MPC
0.36
ClinPred
0.11
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.025
gMVP
0.12

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765915065; hg19: chr14-89629017; COSMIC: COSV54315605; COSMIC: COSV54315605; API