17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTC

Variant names:

• chr17-28523792-TTCTCTCTCTC-T
• rs10527420
• NM_001369369.1:c.-14-133_-14-124delTCTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001369369.1(FOXN1):​c.-14-133_-14-124delTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 644,526 control chromosomes in the GnomAD database, including 15 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene FOXN1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0071 (13 hom., cov: 0)
  • Exomes 𝑓: 0.017 (2 hom.)
• Consequence: FOXN1 NM_001369369.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00713 (1029/144260) while in subpopulation AFR AF = 0.0232 (875/37718). AF 95% confidence interval is 0.0219. There are 13 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 SD,AD,AR gene

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.-14-133_-14-124delTCTCTCTCTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-177_-168delTCTCTCTCTC		upstream_gene	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.-14-163_-14-154delTCTCTCTCTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67693_*1196-67684delGAGAGAGAGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-168_-9-159delTCTCTCTCTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1024 AN: 144160 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00391

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000628

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000973

Gnomad OTH AF: 0.00760

GnomAD4 exome AF: 0.0174 AC: 8724 AN: 500266 Hom.: 2 AF XY: 0.0173 AC XY: 4660 AN XY: 269038

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0613 AC: 841 AN: 13728

American (AMR) AF: 0.0112 AC: 312 AN: 27896

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 358 AN: 17360

East Asian (EAS) AF: 0.00763 AC: 234 AN: 30652

South Asian (SAS) AF: 0.0156 AC: 883 AN: 56478

European-Finnish (FIN) AF: 0.0180 AC: 631 AN: 34996

Middle Eastern (MID) AF: 0.0282 AC: 67 AN: 2376

European-Non Finnish (NFE) AF: 0.0168 AC: 4853 AN: 289072

Other (OTH) AF: 0.0197 AC: 545 AN: 27708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00713 AC: 1029 AN: 144260 Hom.: 13 Cov.: 0 AF XY: 0.00741 AC XY: 518 AN XY: 69902

African (AFR) AF: 0.0232 AC: 875 AN: 37718

American (AMR) AF: 0.00391 AC: 56 AN: 14334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.000629 AC: 3 AN: 4768

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4440

European-Finnish (FIN) AF: 0.00104 AC: 10 AN: 9630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000974 AC: 65 AN: 66768

Other (OTH) AF: 0.00752 AC: 15 AN: 1994

Alfa AF: 0.00 Hom.: 106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10527420; hg19: chr17-26850810;