chr17-28534758-TCCTGGGCTGTCCGCCC-T

Position:

• chr17-28534758-TCCTGGGCTGTCCGCCC-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4 PM2_Supporting PS4 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001369369.1(FOXN1):c.1201_1216del (p.Pro401AlafsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 544. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). This variant is absent from gnomADv2.1.1 (PM2_supporting). This variant has been reported heterozygous in at least 10 patients (PS4) with T lymphopenia, particularly low CD8+ cell counts, at least one of whom also had nail dystrophy (P13 of PMID:31447097; PP4). 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_strong, PM2_supporting, PS4 and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16620352/MONDO:0011132/113

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXN1 NM_001369369.1 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 3.32

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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/exons	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.1201_1216delCCCCCTGGGCTGTCCG	p.Pro401fs	frameshift_variant	8/9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.1201_1216delCCCCCTGGGCTGTCCG	p.Pro401fs	frameshift_variant	8/9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.1201_1216delCCCCCTGGGCTGTCCG	p.Pro401fs	frameshift_variant	7/8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+69277_*1195+69292delGGGCGGACAGCCCAGG		intron_variant		1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.1201_1216delCCCCCTGGGCTGTCCG	p.Pro401fs	frameshift_variant	8/9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2023	This sequence change creates a premature translational stop signal (p.Pro401Alafs*144) in the FOXN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 248 amino acid(s) of the FOXN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with FOXN1 haploinsufficiency (PMID: 31447097, 31566583; Invitae). ClinVar contains an entry for this variant (Variation ID: 418218). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FOXN1 function (PMID: 31566583). This variant disrupts a region of the FOXN1 protein in which other variant(s) (p.Gln489Argfs*61) have been determined to be pathogenic (PMID: 31566583). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jul 29, 2024	The NM_001369369.1(FOXN1):c.1201_1216del (p.Pro401AlafsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 544. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). This variant is absent from gnomADv2.1.1 (PM2_supporting). This variant has been reported heterozygous in at least 10 patients (PS4) with T lymphopenia, particularly low CD8+ cell counts, at least one of whom also had nail dystrophy (P13 of PMID: 31447097; PP4). 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_strong, PM2_supporting, PS4 and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2017

The c.1201_1216del16 variant in the FOXN1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, GeneDx has observed this variant as a de novo heterozygous variant (without a second identifiable FOXN1 variant) in another individual referred for exome analysis. The c.1201_1216del16 variant causes a frameshift starting with codon Proline 401, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 144 of the new reading frame, denoted p.Pro401AlafsX144. This variant is predicted to replace the last 248 amino acids of the protein with 143 incorrect amino acids. The c.1201_1216del16 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064793129; hg19: chr17-26861776;