17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001369369.1(FOXN1):​c.-14-125_-14-124delTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 648,298 control chromosomes in the GnomAD database, including 133 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (132 hom., cov: 0)
  • Exomes 𝑓: 0.0087 (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.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

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_-14-124delTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-177_-176delTC		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_-14-162delTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67685_*1196-67684delGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-168_-9-167delTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3626 AN: 144076 Hom.: 132 Cov.: 0

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.00449

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00134

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00421

Gnomad OTH AF: 0.0228

GnomAD4 exome AF: 0.00872 AC: 4395 AN: 504124 Hom.: 1 AF XY: 0.00881 AC XY: 2389 AN XY: 271022

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

African (AFR) AF: 0.0685 AC: 951 AN: 13878

American (AMR) AF: 0.00725 AC: 203 AN: 28010

Ashkenazi Jewish (ASJ) AF: 0.00319 AC: 56 AN: 17542

East Asian (EAS) AF: 0.00107 AC: 33 AN: 30832

South Asian (SAS) AF: 0.0125 AC: 709 AN: 56568

European-Finnish (FIN) AF: 0.00228 AC: 81 AN: 35458

Middle Eastern (MID) AF: 0.0108 AC: 26 AN: 2400

European-Non Finnish (NFE) AF: 0.00702 AC: 2047 AN: 291548

Other (OTH) AF: 0.0104 AC: 289 AN: 27888

⚠️ 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: 0.0252 AC: 3632 AN: 144174 Hom.: 132 Cov.: 0 AF XY: 0.0240 AC XY: 1674 AN XY: 69866

African (AFR) AF: 0.0832 AC: 3125 AN: 37580

American (AMR) AF: 0.0108 AC: 155 AN: 14330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.000210 AC: 1 AN: 4766

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4438

European-Finnish (FIN) AF: 0.00134 AC: 13 AN: 9668

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00421 AC: 281 AN: 66788

Other (OTH) AF: 0.0226 AC: 45 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		0.097
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10527420; hg19: chr17-26850810;