rs73278523

Positions:

chr17-28537246-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_001369369.1(FOXN1):c.1757G>A (p.Cys586Tyr) has a gnomADv3.1.2 popmax filtering allele frequency of 0.003485 based upon the African/African American population (165/41444 alleles), which is above the BS1 threshold of >0.00141 but below the BA1 threshold of >0.00447 and thus meets BS1. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as likely 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: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459619/MONDO:0011132/113

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

FOXN1
ENST00000579795.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: 3.26

Variant links:

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]

FOXN1 links:

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]

RSKR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS1

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 linkuse as main transcript	c.1757G>A	p.Cys586Tyr	missense_variant	9/9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6 linkuse as main transcript	c.1757G>A	p.Cys586Tyr	missense_variant	9/9	1	NM_001369369.1	ENSP00000464645	P1
FOXN1	ENST00000226247.2 linkuse as main transcript	c.1757G>A	p.Cys586Tyr	missense_variant	8/8	1		ENSP00000226247	P1
RSKR	ENST00000481916.6 linkuse as main transcript	c.*1195+66805C>T		intron_variant, NMD_transcript_variant		1		ENSP00000436369		Q96LW2-2
FOXN1	ENST00000577936.2 linkuse as main transcript	c.1757G>A	p.Cys586Tyr	missense_variant	9/9	4		ENSP00000462159	P1

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000350

AC:

AN:

251210

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1461758

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00451

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152308

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00399

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.00138

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000502

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Benign:3

Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jul 29, 2024	The missense variant NM_001369369.1(FOXN1):c.1757G>A (p.Cys586Tyr) has a gnomADv3.1.2 popmax filtering allele frequency of 0.003485 based upon the African/African American population (165/41444 alleles), which is above the BS1 threshold of >0.00141 but below the BA1 threshold of >0.00447 and thus meets BS1. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as likely 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: BS1. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

.;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.015

T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.94

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.1

.;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.60

MVP

0.93

MPC

0.10

ClinPred

0.045

GERP RS

3.5

Varity_R

0.63

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over