rs1064793129
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4PM2_SupportingPS4PVS1_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
Consequence
NM_001369369.1 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FOXN1 | NM_001369369.1 | c.1201_1216delCCCCCTGGGCTGTCCG | p.Pro401AlafsTer144 | frameshift_variant | Exon 8 of 9 | ENST00000579795.6 | NP_001356298.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FOXN1 | ENST00000579795.6 | c.1201_1216delCCCCCTGGGCTGTCCG | p.Pro401AlafsTer144 | frameshift_variant | Exon 8 of 9 | 1 | NM_001369369.1 | ENSP00000464645.1 | ||
| FOXN1 | ENST00000226247.2 | c.1201_1216delCCCCCTGGGCTGTCCG | p.Pro401AlafsTer144 | frameshift_variant | Exon 7 of 8 | 1 | ENSP00000226247.2 | |||
| RSKR | ENST00000481916.6 | n.*1195+69277_*1195+69292delGGGCGGACAGCCCAGG | intron_variant | Intron 7 of 7 | 1 | ENSP00000436369.2 | ||||
| FOXN1 | ENST00000577936.2 | c.1201_1216delCCCCCTGGGCTGTCCG | p.Pro401AlafsTer144 | frameshift_variant | Exon 8 of 9 | 4 | ENSP00000462159.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461416Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727004
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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. -
FOXN1: PVS1:Strong, PM2, PS4:Moderate -
T-cell immunodeficiency, congenital alopecia, and nail dystrophy Pathogenic:2
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; internal data). ClinVar contains an entry for this variant (Variation ID: 418218). Algorithms developed to predict the effect of variants on gene product 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. -
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. -
T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at