NM_001369369.1:c.1795G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369369.1(FOXN1):c.1795G>C(p.Ala599Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,382 control chromosomes in the GnomAD database, including 81,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A599H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 12481 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69071 hom. )

Consequence

FOXN1
NM_001369369.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.0710

Publications

25 publications found

Variant links:

Genes affected

FOXN1 (HGNC:12765): (forkhead box N1) Mutations in the winged-helix transcription factor gene at the nude locus in mice and rats produce the pleiotropic phenotype of hairlessness and athymia, resulting in a severely compromised immune system. This gene is orthologous to the mouse and rat genes and encodes a similar DNA-binding transcription factor that is thought to regulate keratin gene expression. A mutation in this gene has been correlated with T-cell immunodeficiency, the skin disorder congenital alopecia, and nail dystrophy. Alternative splicing in the 5' UTR of this gene has been observed. [provided by RefSeq, Jul 2008]

FOXN1 links:

RSKR (HGNC:26314): (ribosomal protein S6 kinase related) Predicted to enable protein kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

RSKR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5099122E-5).

BP6

Variant 17-28537284-G-C is Benign according to our data. Variant chr17-28537284-G-C is described in ClinVar as Benign. ClinVar VariationId is 322436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369369.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN1	NM_001369369.1	MANE Select	c.1795G>C	p.Ala599Pro	missense	Exon 9 of 9	NP_001356298.1
	FOXN1	NM_003593.3		c.1795G>C	p.Ala599Pro	missense	Exon 8 of 8	NP_003584.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXN1	ENST00000579795.6	TSL:1 MANE Select	c.1795G>C	p.Ala599Pro	missense	Exon 9 of 9	ENSP00000464645.1
FOXN1	ENST00000226247.2	TSL:1	c.1795G>C	p.Ala599Pro	missense	Exon 8 of 8	ENSP00000226247.2
RSKR	ENST00000481916.6	TSL:1	n.*1195+66767C>G		intron	N/A	ENSP00000436369.2

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57878

AN:

151864

Hom.:

12461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.582

Gnomad AMI

AF:

0.376

Gnomad AMR

AF:

0.386

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.227

Gnomad SAS

AF:

0.302

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.352

GnomAD2 exomes

AF:

0.319

AC:

80065

AN:

250772

AF XY:

0.312

show subpopulations

Gnomad AFR exome

AF:

0.583

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.313

GnomAD4 exome

AF:

0.302

AC:

441861

AN:

1461400

Hom.:

69071

Cov.:

AF XY:

0.301

AC XY:

218978

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.588

AC:

19671

AN:

33472

American (AMR)

AF:

0.360

AC:

16090

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

7270

AN:

26134

East Asian (EAS)

AF:

0.235

AC:

9315

AN:

39698

South Asian (SAS)

AF:

0.305

AC:

26346

AN:

86244

European-Finnish (FIN)

AF:

0.323

AC:

17188

AN:

53282

Middle Eastern (MID)

AF:

0.374

AC:

2156

AN:

5768

European-Non Finnish (NFE)

AF:

0.292

AC:

324854

AN:

1111706

Other (OTH)

AF:

0.314

AC:

18971

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17913

35826

53740

71653

89566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10880

21760

32640

43520

54400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.381

AC:

57939

AN:

151982

Hom.:

12481

Cov.:

AF XY:

0.381

AC XY:

28274

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.582

AC:

24106

AN:

41430

American (AMR)

AF:

0.386

AC:

5897

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1010

AN:

3470

East Asian (EAS)

AF:

0.227

AC:

1168

AN:

5138

South Asian (SAS)

AF:

0.301

AC:

1449

AN:

4812

European-Finnish (FIN)

AF:

0.322

AC:

3416

AN:

10600

Middle Eastern (MID)

AF:

0.363

AC:

106

AN:

292

European-Non Finnish (NFE)

AF:

0.290

AC:

19709

AN:

67938

Other (OTH)

AF:

0.349

AC:

736

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1716

3432

5147

6863

8579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.316

Hom.:

2618

Bravo

AF:

0.393

TwinsUK

AF:

0.289

AC:

1071

ALSPAC

AF:

0.285

AC:

1100

ESP6500AA

AF:

0.569

AC:

2506

ESP6500EA

AF:

0.281

AC:

2419

ExAC

AF:

0.322

AC:

39063

Asia WGS

AF:

0.287

AC:

999

AN:

3478

EpiCase

AF:

0.290

EpiControl

AF:

0.295

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

T-cell immunodeficiency, congenital alopecia, and nail dystrophy (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

5.3

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.11

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.23

MetaRNN

Benign

0.000015

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.90

PhyloP100

0.071

PrimateAI

Benign

0.40

PROVEAN

Benign

1.8

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.033

MPC

0.015

ClinPred

0.00076

GERP RS

2.2

Varity_R

0.061

gMVP

0.13

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over