17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant names:

• chr17-28523792-T-TTCTCTCTCTCTCTCTC
• rs10527420
• NM_001369369.1:c.-14-139_-14-124dupTCTCTCTCTCTCTCTC

Variant summary

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

The NM_001369369.1(FOXN1):​c.-14-139_-14-124dupTCTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 650,458 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. The gene FOXN1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00050 (2 hom., cov: 0)
  • Exomes 𝑓: 0.000069 (0 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

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 = 0.000499 (72/144352) while in subpopulation AFR AF = 0.0014 (53/37740). AF 95% confidence interval is 0.0011. There are 2 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.-14-139_-14-124dupTCTCTCTCTCTCTCTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-178_-177insTCTCTCTCTCTCTCTC		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_-14-163insTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67684_*1196-67683insGAGAGAGAGAGAGAGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-169_-9-168insTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 72 AN: 144252 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.000675

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.000506

GnomAD4 exome AF: 0.0000692 AC: 35 AN: 506106 Hom.: 0 AF XY: 0.0000698 AC XY: 19 AN XY: 272114

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

African (AFR) AF: 0.000570 AC: 8 AN: 14032

American (AMR) AF: 0.0000712 AC: 2 AN: 28078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17592

East Asian (EAS) AF: 0.0000972 AC: 3 AN: 30854

South Asian (SAS) AF: 0.0000877 AC: 5 AN: 57044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35504

Middle Eastern (MID) AF: 0.000415 AC: 1 AN: 2412

European-Non Finnish (NFE) AF: 0.0000513 AC: 15 AN: 292604

Other (OTH) AF: 0.0000357 AC: 1 AN: 27986

⚠️ 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: 0.000499 AC: 72 AN: 144352 Hom.: 2 Cov.: 0 AF XY: 0.000558 AC XY: 39 AN XY: 69948

African (AFR) AF: 0.00140 AC: 53 AN: 37740

American (AMR) AF: 0.000209 AC: 3 AN: 14332

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

East Asian (EAS) AF: 0.000210 AC: 1 AN: 4768

South Asian (SAS) AF: 0.000676 AC: 3 AN: 4440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9668

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

European-Non Finnish (NFE) AF: 0.000165 AC: 11 AN: 66798

Other (OTH) AF: 0.000501 AC: 1 AN: 1996

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

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;