17-28529157-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PP4PM2_SupportingPM3PP1_StrongPVS1

This summary comes from the ClinGen Evidence Repository: The NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter) nonsense variant occurs in exon 5 of 9 and is predicted to result in non-sense mediated decay (PVS1). The highest MAF in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). At least one patient (PMID:10206641) is described with congenital alopecia, nail dystrophy, and very low T cell number which is highly specific to FOXN1 deficiency (PP4). This individual had an affected siblings, also homozygous for the variant, as reported in PMID:10206641. Additionally PMID:31447097 reports another 14 heterozygous relatives with nail dystrophy belonging to same extended family (estimated LOD score 4.82; PP1_Strong). At least two additional unrelated patients have been reported, these three unrelated patients are all homozygous (PMIDs: 28636882, 20978268, 10206641; PM3). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4, PP1_strong, PM3 as specified by the ClinGen SCID VCEP FOXN1 subgroup (specifications v1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA119892/MONDO:0011132/113

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXN1
NM_001369369.1 stop_gained

Scores

2

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 1.61

Publications

15 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: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PM2

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

PM3

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

PP1

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

PP4

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.763C>T	p.Arg255*	stop_gained	Exon 5 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6 link	c.763C>T	p.Arg255*	stop_gained	Exon 5 of 9	1	NM_001369369.1	ENSP00000464645.1		O15353
FOXN1	ENST00000226247.2 link	c.763C>T	p.Arg255*	stop_gained	Exon 4 of 8	1		ENSP00000226247.2		O15353
RSKR	ENST00000481916.6 link	n.*1196-73048G>A		intron_variant	Intron 7 of 7	1		ENSP00000436369.2		Q96LW2-2
FOXN1	ENST00000577936.2 link	c.763C>T	p.Arg255*	stop_gained	Exon 5 of 9	4		ENSP00000462159.2		O15353J3KRT9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152188

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

1

AN:

251486

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

2

AN:

1461864

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

2

AN:

1111986

Other (OTH)

AF:

0.00

AC:

0

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<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:

0.00000657

AC:

1

AN:

152188

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41440

American (AMR)

AF:

0.00

AC:

0

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4836

European-Finnish (FIN)

AF:

0.0000942

AC:

1

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68028

Other (OTH)

AF:

0.00

AC:

0

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Pathogenic:3

Jun 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg255*) in the FOXN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXN1 are known to be pathogenic (PMID: 10206641, 15180707, 31447097). This variant is present in population databases (rs104894562, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency, alopecia, and nail dystrophy (PMID: 10206641, 15180707, 20864124, 20978268, 21507891, 28636882). It is commonly reported in individuals of Italian ancestry (PMID: 15180707). ClinVar contains an entry for this variant (Variation ID: 8757). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jul 29, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter) nonsense variant occurs in exon 5 of 9 and is predicted to result in non-sense mediated decay (PVS1). The highest MAF in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). At least one patient (PMID: 10206641) is described with congenital alopecia, nail dystrophy, and very low T cell number which is highly specific to FOXN1 deficiency (PP4). This individual had an affected siblings, also homozygous for the variant, as reported in PMID: 10206641. Additionally PMID: 31447097 reports another 14 heterozygous relatives with nail dystrophy belonging to same extended family (estimated LOD score 4.82; PP1_Strong). At least two additional unrelated patients have been reported, these three unrelated patients are all homozygous (PMIDs: 28636882, 20978268, 10206641; PM3). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4, PP1_strong, PM3 as specified by the ClinGen SCID VCEP FOXN1 subgroup (specifications v1.0). -

Severe combined immunodeficiency disease

Pathogenic:1

Oct 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FOXN1 c.763C>T (p.Arg255X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 251486 control chromosomes. c.763C>T has been reported in the literature in individuals affected with Severe Combined Immunodeficiency (example, Frank_1999). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 10206641). ClinVar contains an entry for this variant (Variation ID: 8757). Based on the evidence outlined above, the variant was classified as pathogenic. -

T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant

Pathogenic:1

Jun 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

D

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

39

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.97

D

PhyloP100

1.6

Vest4

0.81

GERP RS

3.7

Mutation Taster

=2/198

disease causing (ClinVar)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs104894562; hg19: chr17-26856175; API