rs2071587

chr17-28524584-C-T

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.205C>T(p.Arg69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0891 in 1,613,542 control chromosomes in the GnomAD database, including 8,040 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (772 hom., cov: 33)
  • Exomes 𝑓: 0.090 (7268 hom.)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 3.08

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 (MetaRNN=0.0015019178).
• BP6: Variant 17-28524584-C-T is Benign according to our data. Variant chr17-28524584-C-T is described in ClinVar as [Benign]. Clinvar id is 322414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN1	NM_001369369.1	c.205C>T	p.Arg69Cys	missense_variant	3/9	ENST00000579795.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN1	ENST00000579795.6	c.205C>T	p.Arg69Cys	missense_variant	3/9	1	NM_001369369.1	P1
FOXN1	ENST00000226247.2	c.205C>T	p.Arg69Cys	missense_variant	2/8	1		P1
RSKR	ENST00000481916.6	c.*1196-68475G>A		intron_variant, NMD_transcript_variant		1
FOXN1	ENST00000577936.2	c.205C>T	p.Arg69Cys	missense_variant	3/9	4		P1

Frequencies

GnomAD3 genomes AF: 0.0814 AC: 12381 AN: 152154 Hom.: 768 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0941

GnomAD3 exomes AF: 0.110 AC: 27541 AN: 250372 Hom.: 2198 AF XY: 0.104 AC XY: 14064 AN XY: 135526

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.203

Gnomad SAS exome AF: 0.0720

Gnomad FIN exome AF: 0.0966

Gnomad NFE exome AF: 0.0814

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.0899 AC: 131401 AN: 1461270 Hom.: 7268 Cov.: 35 AF XY: 0.0883 AC XY: 64167 AN XY: 726972

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.0603

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.0721

Gnomad4 FIN exome AF: 0.0934

Gnomad4 NFE exome AF: 0.0832

Gnomad4 OTH exome AF: 0.0899

GnomAD4 genome AF: 0.0814 AC: 12391 AN: 152272 Hom.: 772 Cov.: 33 AF XY: 0.0853 AC XY: 6353 AN XY: 74458

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.0665

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.0714

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0825

Gnomad4 OTH AF: 0.0931

Alfa AF: 0.0866 Hom.: 1278

Bravo AF: 0.0862

TwinsUK AF: 0.0763 AC: 283

ALSPAC AF: 0.0804 AC: 310

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0759 AC: 653

ExAC AF: 0.101 AC: 12278

Asia WGS AF: 0.101 AC: 350 AN: 3478

EpiCase AF: 0.0817

EpiControl AF: 0.0793

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2015	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. -
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 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.74	T;.;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.24	P;P
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.078	T;D;D
Polyphen		0.021	.;B;B
Vest4		0.059, 0.061
MPC		0.20
ClinPred		0.12	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs2071587; hg19: chr17-26851602; COSMIC: COSV56880923;