rs1064793129
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001369369.1(FOXN1):c.1201_1216del(p.Pro401AlafsTer144) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FOXN1
NM_001369369.1 frameshift
NM_001369369.1 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 17-28534758-TCCTGGGCTGTCCGCCC-T is Pathogenic according to our data. Variant chr17-28534758-TCCTGGGCTGTCCGCCC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXN1 | NM_001369369.1 | c.1201_1216del | p.Pro401AlafsTer144 | frameshift_variant | 8/9 | ENST00000579795.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXN1 | ENST00000579795.6 | c.1201_1216del | p.Pro401AlafsTer144 | frameshift_variant | 8/9 | 1 | NM_001369369.1 | P1 | |
FOXN1 | ENST00000226247.2 | c.1201_1216del | p.Pro401AlafsTer144 | frameshift_variant | 7/8 | 1 | P1 | ||
RSKR | ENST00000481916.6 | c.*1195+69277_*1195+69292del | intron_variant, NMD_transcript_variant | 1 | |||||
FOXN1 | ENST00000577936.2 | c.1201_1216del | p.Pro401AlafsTer144 | frameshift_variant | 8/9 | 4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
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 exome
Data not reliable, filtered out with message: AC0
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727004
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
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 immunodeficiency, congenital alopecia, and nail dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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. - |
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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at