14-89162709-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005197.4(FOXN3):c.1112C>T(p.Thr371Met) variant causes a missense change. The variant allele was found at a frequency of 0.000143 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: FOXN3 NM_005197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016339242).
• BS2: High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN3	NM_005197.4	c.1112C>T	p.Thr371Met	missense_variant	6/6	ENST00000557258.6
FOXN3	NM_001085471.2	c.1178C>T	p.Thr393Met	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN3	ENST00000557258.6	c.1112C>T	p.Thr371Met	missense_variant	6/6	1	NM_005197.4	A1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000224 AC: 56 AN: 250182 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135320

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727212

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000881

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.000323 AC XY: 24 AN XY: 74406

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.00

EpiControl AF: 0.000237

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

Sep 16, 2021

The c.1178C>T (p.T393M) 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 1178, causing the threonine (T) at amino acid position 393 to be replaced by a methionine (M). 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	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.098	T;T;.;.;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.4	L;L;.;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.11	N;N;N;.;N
REVEL	Benign	0.15
Sift	Benign	0.31	T;T;T;.;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.58	P;P;B;B;B
Vest4		0.12
MVP		0.61
MPC		0.92
ClinPred		0.11	T
GERP RS		5.9
Varity_R		0.026
gMVP		0.18

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: rs369372657; hg19: chr14-89629053; COSMIC: COSV54304486; COSMIC: COSV54304486;