rs1555609768

Positions:

• chr17-28527362-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_001369369.1(FOXN1):c.699+1G>T intron 4 donor splice site variant is predicted to result in skipping of exon 4 causing an in frame deletion of Gly197 to Gln233, accounting for 5.7% of the protein (PVS1_Moderate). This variant is absent from gnomADv2.1.1 (PM2_supporting). There is one entry for this variant in ClinVar (SCV000766592.5) but it has not been reported in the literature in individuals with FOXN1-related disease. In summary this variant meets criteria to be classified as uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_Moderate and PM2_Supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. LINK:https://erepo.genome.network/evrepo/ui/classification/CA398322535/MONDO:0011132/113

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXN1 NM_001369369.1 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 6.07

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.699+1G>T		splice_donor_variant, intron_variant		ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.699+1G>T		splice_donor_variant, intron_variant		1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.699+1G>T		splice_donor_variant, intron_variant		1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1196-71253C>A		intron_variant		1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.699+1G>T		splice_donor_variant, intron_variant		4		ENSP00000462159.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2019	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FOXN1 are known to be pathogenic (PMID: 10206641, 15180707). This variant has not been reported in the literature in individuals with FOXN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the FOXN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jul 29, 2024	The NM_001369369.1(FOXN1):c.699+1G>T intron 4 donor splice site variant is predicted to result in skipping of exon 4 causing an in frame deletion of Gly197 to Gln233, accounting for 5.7% of the protein (PVS1_Moderate). This variant is absent from gnomADv2.1.1 (PM2_supporting). There is one entry for this variant in ClinVar (SCV000766592.5) but it has not been reported in the literature in individuals with FOXN1-related disease. In summary this variant meets criteria to be classified as uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_Moderate and PM2_Supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555609768; hg19: chr17-26854380;