chr17-28534546-C-T

Variant names:

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.1135+8C>T		splice_region_variant, intron_variant	Intron 7 of 8	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.1135+8C>T		splice_region_variant, intron_variant	Intron 7 of 8	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.1135+8C>T		splice_region_variant, intron_variant	Intron 6 of 7	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+69505G>A		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.1135+8C>T		splice_region_variant, intron_variant	Intron 7 of 8	4		ENSP00000462159.2

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

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 29, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;