17-28523911-A-C

Position:

• chr17-28523911-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369369.1(FOXN1):​c.-14-45A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.934 in 1,610,276 control chromosomes in the GnomAD database, including 703,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64010 hom., cov: 28)
  • Exomes 𝑓: 0.94 (639023 hom.)
• Consequence: FOXN1 NM_001369369.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.376

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-28523911-A-C is Benign according to our data. Variant chr17-28523911-A-C is described in ClinVar as [Benign]. Clinvar id is 1182314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN1	NM_001369369.1	c.-14-45A>C		intron_variant		ENST00000579795.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN1	ENST00000579795.6	c.-14-45A>C		intron_variant		1	NM_001369369.1	P1
RSKR	ENST00000481916.6	c.*1196-67802T>G		intron_variant, NMD_transcript_variant		1
FOXN1	ENST00000577936.2	c.-9-50A>C		intron_variant		4		P1
FOXN1	ENST00000226247.2			upstream_gene_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139074 AN: 151522 Hom.: 63975 Cov.: 28

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.955

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.978

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.944

Gnomad OTH AF: 0.911

GnomAD4 exome AF: 0.935 AC: 1364320 AN: 1458636 Hom.: 639023 Cov.: 35 AF XY: 0.932 AC XY: 676438 AN XY: 725794

Gnomad4 AFR exome AF: 0.847

Gnomad4 AMR exome AF: 0.962

Gnomad4 ASJ exome AF: 0.945

Gnomad4 EAS exome AF: 0.986

Gnomad4 SAS exome AF: 0.824

Gnomad4 FIN exome AF: 0.975

Gnomad4 NFE exome AF: 0.942

Gnomad4 OTH exome AF: 0.929

GnomAD4 genome AF: 0.918 AC: 139163 AN: 151640 Hom.: 64010 Cov.: 28 AF XY: 0.919 AC XY: 68108 AN XY: 74114

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.955

Gnomad4 ASJ AF: 0.941

Gnomad4 EAS AF: 0.976

Gnomad4 SAS AF: 0.820

Gnomad4 FIN AF: 0.978

Gnomad4 NFE AF: 0.944

Gnomad4 OTH AF: 0.906

Alfa AF: 0.942 Hom.: 19960

Bravo AF: 0.916

Asia WGS AF: 0.886 AC: 3078 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 67% of patients studied by a panel of primary immunodeficiencies. Number of patients: 64. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	13
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs483434; hg19: chr17-26850929;