17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant names:

• chr17-28523792-T-TTCTC
• rs10527420
• NM_001369369.1:c.-14-127_-14-124dupTCTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001369369.1(FOXN1):​c.-14-127_-14-124dupTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 642,398 control chromosomes in the GnomAD database, including 63 homozygotes. Variant has been reported in ClinVar as Likely benign (★). The gene FOXN1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.017 (38 hom., cov: 0)
  • Exomes 𝑓: 0.017 (25 hom.)
• Consequence: FOXN1 NM_001369369.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 17-28523792-T-TTCTC is Benign according to our data. Variant chr17-28523792-T-TTCTC is described in ClinVar as Likely_benign. ClinVar VariationId is 1706676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0174 (2504/144186) while in subpopulation AMR AF = 0.0485 (692/14282). AF 95% confidence interval is 0.0455. There are 38 homozygotes in GnomAd4. There are 1248 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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.-14-127_-14-124dupTCTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-178_-177insTCTC		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_-14-163insTCTC		intron	N/A	ENSP00000464645.1	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-67684_*1196-67683insGAGA		intron	N/A	ENSP00000436369.2	Q96LW2-2
	FOXN1	ENST00000577936.2	TSL:4	c.-9-169_-9-168insTCTC		intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2498 AN: 144088 Hom.: 38 Cov.: 0

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.00554

Gnomad EAS AF: 0.0134

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00891

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.0172 AC: 8557 AN: 498212 Hom.: 25 AF XY: 0.0164 AC XY: 4392 AN XY: 268100

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

African (AFR) AF: 0.0223 AC: 308 AN: 13832

American (AMR) AF: 0.0639 AC: 1730 AN: 27084

Ashkenazi Jewish (ASJ) AF: 0.00648 AC: 113 AN: 17444

East Asian (EAS) AF: 0.0309 AC: 914 AN: 29558

South Asian (SAS) AF: 0.0146 AC: 828 AN: 56614

European-Finnish (FIN) AF: 0.0153 AC: 534 AN: 34978

Middle Eastern (MID) AF: 0.0130 AC: 31 AN: 2376

European-Non Finnish (NFE) AF: 0.0126 AC: 3634 AN: 288772

Other (OTH) AF: 0.0169 AC: 465 AN: 27554

⚠️ 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: 0.0174 AC: 2504 AN: 144186 Hom.: 38 Cov.: 0 AF XY: 0.0179 AC XY: 1248 AN XY: 69858

African (AFR) AF: 0.0222 AC: 837 AN: 37682

American (AMR) AF: 0.0485 AC: 692 AN: 14282

Ashkenazi Jewish (ASJ) AF: 0.00554 AC: 19 AN: 3430

East Asian (EAS) AF: 0.0134 AC: 64 AN: 4764

South Asian (SAS) AF: 0.0133 AC: 59 AN: 4434

European-Finnish (FIN) AF: 0.00891 AC: 86 AN: 9656

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

European-Non Finnish (NFE) AF: 0.0106 AC: 707 AN: 66762

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

Alfa AF: 0.0114 Hom.: 106

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;