chr17-28524584-C-T

Position:

• chr17-28524584-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_001369369.1(FOXN1):c.205C>T is predicted to cause an arginine to cysteine substitution at amino acid position 69. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. The variant has a gnomAD popmax filtering allele frequency of 0.2496 based upon the Latino population, which is greater than 0.00447 and thus meets BA1. Additionally, the in-silico meta predictor REVEL suggests the variant has no effect on gene function with a score of 0.277, which is less than 0.290 and thus meets BP4. The variant is associated with the following publication: PMID:18006695. In summary, this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4 and BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459177/MONDO:0011132/113

• Frequency:
  • Genomes: 𝑓 0.081 (772 hom., cov: 33)
  • Exomes 𝑓: 0.090 (7268 hom.)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Benign reviewed by expert panel B:7 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.205C>T	p.Arg69Cys	missense_variant	3/9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.205C>T	p.Arg69Cys	missense_variant	3/9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.205C>T	p.Arg69Cys	missense_variant	2/8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1196-68475G>A		intron_variant		1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.205C>T	p.Arg69Cys	missense_variant	3/9	4		ENSP00000462159.2

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:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

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 -
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. -

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Benign:3

Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jul 29, 2024	The variant NM_001369369.1(FOXN1):c.205C>T is predicted to cause an arginine to cysteine substitution at amino acid position 69. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. The variant has a gnomAD popmax filtering allele frequency of 0.2496 based upon the Latino population, which is greater than 0.00447 and thus meets BA1. Additionally, the in-silico meta predictor REVEL suggests the variant has no effect on gene function with a score of 0.277, which is less than 0.290 and thus meets BP4. The variant is associated with the following publication: PMID:18006695. In summary, this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4 and BA1. -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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
DEOGEN2	Benign	0.12	.;T;T
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
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.80	.;.;N
REVEL	Benign	0.28
Sift	Uncertain	0.0020	.;.;D
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;