14-89412338-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_005197.4(FOXN3):c.139G>C(p.Asp47His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: FOXN3 NM_005197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27277464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN3	NM_005197.4	c.139G>C	p.Asp47His	missense_variant	2/6	ENST00000557258.6
FOXN3	NM_001085471.2	c.139G>C	p.Asp47His	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN3	ENST00000557258.6	c.139G>C	p.Asp47His	missense_variant	2/6	1	NM_005197.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000166

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

Mar 06, 2023

The c.139G>C (p.D47H) alteration is located in exon 2 (coding exon 1) of the FOXN3 gene. This alteration results from a G to C substitution at nucleotide position 139, causing the aspartic acid (D) at amino acid position 47 to be replaced by a histidine (H). 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	0.13
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;.;.;.;T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.6	L;L;L;L;L;.;.;.
MutationTaster	Benign	0.69	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N;N;.;N;N;N;D
REVEL	Benign	0.14
Sift	Benign	0.096	T;T;T;.;T;T;T;D
Sift4G	Benign	0.076	T;T;T;T;T;T;.;.
Polyphen		0.86	P;P;P;P;P;.;.;.
Vest4		0.14
MutPred		0.34		Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);Loss of disorder (P = 0.0614);
MVP		0.72
MPC		0.82
ClinPred		0.56	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1891564748; hg19: chr14-89878682; COSMIC: COSV54315219; COSMIC: COSV54315219;