rs1555609768

Variant names:

• chr17-28527362-G-T
• rs1555609768
• NM_001369369.1:c.699+1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Specifications for FOXN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369369.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN1	NM_001369369.1	MANE Select	c.699+1G>T		splice_donor intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.699+1G>T		splice_donor intron	N/A	NP_003584.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN1	ENST00000579795.6	TSL:1 MANE Select	c.699+1G>T		splice_donor intron	N/A	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.699+1G>T		splice_donor intron	N/A	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-71253C>A		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.1
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

Other links and lift over

dbSNP: rs1555609768; hg19: chr17-26854380;