rs2071587

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_001369369.1(FOXN1):c.205C>T is predicted to cause an arginine to cysteine substitution at amino acid position 69. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. The variant has a gnomAD popmax filtering allele frequency of 0.2496 based upon the Latino population, which is greater than 0.00447 and thus meets BA1. Additionally, the in-silico meta predictor REVEL suggests the variant has no effect on gene function with a score of 0.277, which is less than 0.290 and thus meets BP4. The variant is associated with the following publication: PMID:18006695. In summary, this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4 and BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459177/MONDO:0011132/113

Frequency

Genomes: 𝑓 0.081 ( 772 hom., cov: 33)

Exomes 𝑓: 0.090 ( 7268 hom. )

Consequence

FOXN1
NM_001369369.1 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: 3.08

Publications

27 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 -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 3 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FOXN1	ENST00000579795.6 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 3 of 9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 2 of 8	1		ENSP00000226247.2
RSKR	ENST00000481916.6 link	n.*1196-68475G>A		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 3 of 9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes

AF:

0.0814

AC:

12381

AN:

152154

Hom.:

768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0218

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.188

Gnomad ASJ

AF:

0.0665

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.0722

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0825

Gnomad OTH

AF:

0.0941

GnomAD2 exomes

AF:

0.110

AC:

27541

AN:

250372

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.0209

Gnomad AMR exome

AF:

0.254

Gnomad ASJ exome

AF:

0.0614

Gnomad EAS exome

AF:

0.203

Gnomad FIN exome

AF:

0.0966

Gnomad NFE exome

AF:

0.0814

Gnomad OTH exome

AF:

0.0967

GnomAD4 exome

AF:

0.0899

AC:

131401

AN:

1461270

Hom.:

7268

Cov.:

AF XY:

0.0883

AC XY:

64167

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.0169

AC:

565

AN:

33478

American (AMR)

AF:

0.249

AC:

11120

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0603

AC:

1577

AN:

26136

East Asian (EAS)

AF:

0.220

AC:

8736

AN:

39698

South Asian (SAS)

AF:

0.0721

AC:

6218

AN:

86254

European-Finnish (FIN)

AF:

0.0934

AC:

4940

AN:

52902

Middle Eastern (MID)

AF:

0.0567

AC:

327

AN:

5766

European-Non Finnish (NFE)

AF:

0.0832

AC:

92490

AN:

1111924

Other (OTH)

AF:

0.0899

AC:

5428

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

6895

13790

20686

27581

34476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3572

7144

10716

14288

17860

<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:

0.0814

AC:

12391

AN:

152272

Hom.:

772

Cov.:

AF XY:

0.0853

AC XY:

6353

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0218

AC:

907

AN:

41576

American (AMR)

AF:

0.188

AC:

2883

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0665

AC:

231

AN:

3472

East Asian (EAS)

AF:

0.202

AC:

1039

AN:

5148

South Asian (SAS)

AF:

0.0714

AC:

345

AN:

4830

European-Finnish (FIN)

AF:

0.102

AC:

1085

AN:

10616

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0825

AC:

5612

AN:

68006

Other (OTH)

AF:

0.0931

AC:

197

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

573

1145

1718

2290

2863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0869

Hom.:

1873

Bravo

AF:

0.0862

TwinsUK

AF:

0.0763

AC:

283

ALSPAC

AF:

0.0804

AC:

310

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.0759

AC:

653

ExAC

AF:

0.101

AC:

12278

Asia WGS

AF:

0.101

AC:

350

AN:

3478

EpiCase

AF:

0.0817

EpiControl

AF:

0.0793

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 25, 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 -

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 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

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. -

Jul 29, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The variant NM_001369369.1(FOXN1):c.205C>T is predicted to cause an arginine to cysteine substitution at amino acid position 69. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. The variant has a gnomAD popmax filtering allele frequency of 0.2496 based upon the Latino population, which is greater than 0.00447 and thus meets BA1. Additionally, the in-silico meta predictor REVEL suggests the variant has no effect on gene function with a score of 0.277, which is less than 0.290 and thus meets BP4. The variant is associated with the following publication: PMID:18006695. In summary, this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4 and BA1. -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.74

T;.;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N

PhyloP100

3.1

PrimateAI

Benign

0.46

PROVEAN

Benign

0.80

.;.;N

REVEL

Benign

0.28

Sift

Uncertain

0.0020

.;.;D

Sift4G

Benign

0.078

T;D;D

Polyphen

0.021

.;B;B

Vest4

0.059, 0.061

MPC

0.20

ClinPred

0.12

GERP RS

3.3

Varity_R

0.19

gMVP

0.27

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over