17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant names:

• chr17-28523792-T-TTC
• rs10527420
• NM_001369369.1:c.-14-125_-14-124dupTC

Variant summary

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

The NM_001369369.1(FOXN1):​c.-14-125_-14-124dupTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 647,678 control chromosomes in the GnomAD database, including 36 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (35 hom., cov: 0)
  • Exomes 𝑓: 0.0095 (1 hom.)
• Consequence: FOXN1 NM_001369369.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970
• 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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2023/144218) while in subpopulation AFR AF = 0.0325 (1225/37658). AF 95% confidence interval is 0.031. There are 35 homozygotes in GnomAd4. There are 983 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AD,AR,SD 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.-14-125_-14-124dupTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-178_-177insTC		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.-14-164_-14-163insTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67684_*1196-67683insGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-169_-9-168insTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2010 AN: 144122 Hom.: 34 Cov.: 0

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00643

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.0289

Gnomad FIN AF: 0.00342

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00668

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.00950 AC: 4784 AN: 503460 Hom.: 1 AF XY: 0.00999 AC XY: 2704 AN XY: 270666

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

African (AFR) AF: 0.0251 AC: 350 AN: 13944

American (AMR) AF: 0.0185 AC: 513 AN: 27722

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 20 AN: 17560

East Asian (EAS) AF: 0.0141 AC: 430 AN: 30532

South Asian (SAS) AF: 0.0210 AC: 1189 AN: 56616

European-Finnish (FIN) AF: 0.00495 AC: 175 AN: 35378

Middle Eastern (MID) AF: 0.00540 AC: 13 AN: 2406

European-Non Finnish (NFE) AF: 0.00630 AC: 1836 AN: 291446

Other (OTH) AF: 0.00926 AC: 258 AN: 27856

⚠️ 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: 0.0140 AC: 2023 AN: 144218 Hom.: 35 Cov.: 0 AF XY: 0.0141 AC XY: 983 AN XY: 69874

African (AFR) AF: 0.0325 AC: 1225 AN: 37658

American (AMR) AF: 0.00642 AC: 92 AN: 14328

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 4 AN: 3430

East Asian (EAS) AF: 0.0124 AC: 59 AN: 4764

South Asian (SAS) AF: 0.0282 AC: 125 AN: 4426

European-Finnish (FIN) AF: 0.00342 AC: 33 AN: 9660

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.00668 AC: 446 AN: 66776

Other (OTH) AF: 0.0185 AC: 37 AN: 1996

Alfa AF: 0.00604 Hom.: 106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.097
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;