rs2286521

Variant names:

• chr17-28534546-C-T
• rs2286521
• NM_001369369.1:c.1135+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-28534546-C-T
• chr17-28534546-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369369.1(FOXN1):​c.1135+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 1,611,128 control chromosomes in the GnomAD database, including 8,392 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2555 hom., cov: 31)
  • Exomes 𝑓: 0.078 (5837 hom.)
• Consequence: FOXN1 NM_001369369.1 splice_region, intron
• Scores: Splicing: ADA: 0.00002985
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.446
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-28534546-C-T is Benign according to our data. Variant chr17-28534546-C-T is described in ClinVar as Benign. ClinVar VariationId is 322427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 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.1135+8C>T		splice_region intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.1135+8C>T		splice_region intron	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.1135+8C>T		splice_region intron	N/A	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.1135+8C>T		splice_region intron	N/A	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1195+69505G>A		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22447 AN: 150834 Hom.: 2545 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.0452

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0730

Gnomad FIN AF: 0.0963

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0678

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.100 AC: 24891 AN: 248320 AF XY: 0.0932

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.0665

Gnomad OTH exome AF: 0.0789

GnomAD4 exome AF: 0.0782 AC: 114238 AN: 1460186 Hom.: 5837 Cov.: 35 AF XY: 0.0765 AC XY: 55559 AN XY: 726358

African (AFR) AF: 0.318 AC: 10621 AN: 33422

American (AMR) AF: 0.156 AC: 6946 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 1279 AN: 26118

East Asian (EAS) AF: 0.103 AC: 4097 AN: 39686

South Asian (SAS) AF: 0.0697 AC: 6009 AN: 86182

European-Finnish (FIN) AF: 0.0863 AC: 4598 AN: 53294

Middle Eastern (MID) AF: 0.0724 AC: 367 AN: 5068

European-Non Finnish (NFE) AF: 0.0673 AC: 74858 AN: 1111576

Other (OTH) AF: 0.0906 AC: 5463 AN: 60274

GnomAD4 genome AF: 0.149 AC: 22507 AN: 150942 Hom.: 2555 Cov.: 31 AF XY: 0.150 AC XY: 11072 AN XY: 73638

African (AFR) AF: 0.320 AC: 13117 AN: 40956

American (AMR) AF: 0.153 AC: 2322 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3468

East Asian (EAS) AF: 0.120 AC: 615 AN: 5122

South Asian (SAS) AF: 0.0719 AC: 344 AN: 4782

European-Finnish (FIN) AF: 0.0963 AC: 990 AN: 10276

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0679 AC: 4603 AN: 67822

Other (OTH) AF: 0.122 AC: 256 AN: 2092

Alfa AF: 0.0896 Hom.: 886

Bravo AF: 0.158

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (2)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.36
DANN	Benign	0.69
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs2286521; hg19: chr17-26861564; COSMIC: COSV107313434;