17-28537284-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1 link	c.1795G>C	p.Ala599Pro	missense_variant	Exon 9 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXN1	ENST00000579795.6 link	c.1795G>C	p.Ala599Pro	missense_variant	Exon 9 of 9	1	NM_001369369.1	ENSP00000464645.1	O15353
FOXN1	ENST00000226247.2 link	c.1795G>C	p.Ala599Pro	missense_variant	Exon 8 of 8	1		ENSP00000226247.2	O15353
RSKR	ENST00000481916.6 link	n.*1195+66767C>G		intron_variant	Intron 7 of 7	1		ENSP00000436369.2	Q96LW2-2
FOXN1	ENST00000577936.2 link	c.1795G>C	p.Ala599Pro	missense_variant	Exon 9 of 9	4		ENSP00000462159.2	O15353J3KRT9

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

GnomAD3 exomes

AF:

0.319

AC:

80065

AN:

250772

Hom.:

13606

AF XY:

0.312

AC XY:

42369

AN XY:

135642

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 SAS exome

AF:

0.309

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

Gnomad4 AFR exome

AF:

0.588

Gnomad4 AMR exome

AF:

0.360

Gnomad4 ASJ exome

AF:

0.278

Gnomad4 EAS exome

AF:

0.235

Gnomad4 SAS exome

AF:

0.305

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.292

Gnomad4 OTH exome

AF:

0.314

GnomAD4 genome

AF:

0.381

AC:

57939

AN:

151982

Hom.:

12481

Cov.:

AF XY:

0.381

AC XY:

28274

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.582

Gnomad4 AMR

AF:

0.386

Gnomad4 ASJ

AF:

0.291

Gnomad4 EAS

AF:

0.227

Gnomad4 SAS

AF:

0.301

Gnomad4 FIN

AF:

0.322

Gnomad4 NFE

AF:

0.290

Gnomad4 OTH

AF:

0.349

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

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Oct 20, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

5.3

DANN

Benign

0.57

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.23

.;T

MetaRNN

Benign

0.000015

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.90

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

1.8

.;N

REVEL

Benign

0.20

Sift

Benign

1.0

.;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0

B;B

Vest4

0.033

MPC

0.015

ClinPred

0.00076

GERP RS

2.2

Varity_R

0.061

gMVP

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over