17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTC

Variant names:

• chr17-28523792-TTCTCTCTCTCTCTCTCTC-T
• rs10527420
• NM_001369369.1:c.-14-141_-14-124delTCTCTCTCTCTCTCTCTC

Variant summary

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

The NM_001369369.1(FOXN1):​c.-14-141_-14-124delTCTCTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 568,938 control chromosomes in the GnomAD database, including 36 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 0)
  • Exomes 𝑓: 0.062 (35 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

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

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000535 (77/143944) while in subpopulation AFR AF = 0.00119 (45/37728). AF 95% confidence interval is 0.000916. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.-14-141_-14-124delTCTCTCTCTCTCTCTCTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-177_-160delTCTCTCTCTCTCTCTCTC		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_-14-146delTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67701_*1196-67684delGAGAGAGAGAGAGAGAGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-168_-9-151delTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.000535 AC: 77 AN: 143848 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000210

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000300

Gnomad OTH AF: 0.000508

GnomAD4 exome AF: 0.0624 AC: 26534 AN: 424994 Hom.: 35 AF XY: 0.0628 AC XY: 14367 AN XY: 228936

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

African (AFR) AF: 0.0201 AC: 266 AN: 13206

American (AMR) AF: 0.0420 AC: 1065 AN: 25350

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1004 AN: 14792

East Asian (EAS) AF: 0.0583 AC: 1457 AN: 25004

South Asian (SAS) AF: 0.0523 AC: 2606 AN: 49820

European-Finnish (FIN) AF: 0.0602 AC: 1794 AN: 29800

Middle Eastern (MID) AF: 0.0434 AC: 91 AN: 2096

European-Non Finnish (NFE) AF: 0.0698 AC: 16856 AN: 241444

Other (OTH) AF: 0.0594 AC: 1395 AN: 23482

⚠️ 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: 0.000535 AC: 77 AN: 143944 Hom.: 1 Cov.: 0 AF XY: 0.000517 AC XY: 36 AN XY: 69688

African (AFR) AF: 0.00119 AC: 45 AN: 37728

American (AMR) AF: 0.000210 AC: 3 AN: 14304

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3424

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4436

European-Finnish (FIN) AF: 0.000631 AC: 6 AN: 9506

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

European-Non Finnish (NFE) AF: 0.000300 AC: 20 AN: 66610

Other (OTH) AF: 0.000503 AC: 1 AN: 1990

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;