17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant names:

• chr17-28523792-T-TTCTCTCTC
• rs10527420
• NM_001369369.1:c.-14-131_-14-124dupTCTCTCTC

Variant summary

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

The NM_001369369.1(FOXN1):​c.-14-131_-14-124dupTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 649,048 control chromosomes in the GnomAD database, including 17 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 0.0079 (11 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (6 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 eas. GnomAd4 allele frequency = 0.00786 (1133/144224) while in subpopulation EAS AF = 0.0164 (78/4760). AF 95% confidence interval is 0.0137. There are 11 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.-14-131_-14-124dupTCTCTCTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-178_-177insTCTCTCTC		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_-14-163insTCTCTCTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67684_*1196-67683insGAGAGAGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-169_-9-168insTCTCTCTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1137 AN: 144124 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0113

Gnomad AMR AF: 0.00685

Gnomad ASJ AF: 0.00904

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00428

Gnomad FIN AF: 0.00259

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00470

Gnomad OTH AF: 0.00457

GnomAD4 exome AF: 0.00426 AC: 2149 AN: 504824 Hom.: 6 AF XY: 0.00401 AC XY: 1088 AN XY: 271472

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

African (AFR) AF: 0.0105 AC: 147 AN: 13946

American (AMR) AF: 0.00754 AC: 211 AN: 27992

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 69 AN: 17526

East Asian (EAS) AF: 0.0101 AC: 309 AN: 30598

South Asian (SAS) AF: 0.00346 AC: 197 AN: 56954

European-Finnish (FIN) AF: 0.00401 AC: 142 AN: 35454

Middle Eastern (MID) AF: 0.00249 AC: 6 AN: 2406

European-Non Finnish (NFE) AF: 0.00314 AC: 918 AN: 292034

Other (OTH) AF: 0.00537 AC: 150 AN: 27914

⚠️ 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: 0.00786 AC: 1133 AN: 144224 Hom.: 11 Cov.: 0 AF XY: 0.00758 AC XY: 530 AN XY: 69886

African (AFR) AF: 0.0147 AC: 553 AN: 37676

American (AMR) AF: 0.00670 AC: 96 AN: 14318

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 31 AN: 3430

East Asian (EAS) AF: 0.0164 AC: 78 AN: 4760

South Asian (SAS) AF: 0.00383 AC: 17 AN: 4434

European-Finnish (FIN) AF: 0.00259 AC: 25 AN: 9656

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

European-Non Finnish (NFE) AF: 0.00470 AC: 314 AN: 66782

Other (OTH) AF: 0.00452 AC: 9 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		0.097
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;