rs12449554

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001369369.1(FOXN1):c.852T>C(p.Leu284=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,603,446 control chromosomes in the GnomAD database, including 8,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 865 hom., cov: 32)

Exomes 𝑓: 0.091 ( 7544 hom. )

Consequence

FOXN1
NM_001369369.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.167

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 17-28530770-T-C is Benign according to our data. Variant chr17-28530770-T-C is described in ClinVar as [Benign]. Clinvar id is 322425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-28530770-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.167 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN1	NM_001369369.1 linkuse as main transcript	c.852T>C	p.Leu284=	synonymous_variant	6/9	ENST00000579795.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN1	ENST00000579795.6 linkuse as main transcript	c.852T>C	p.Leu284=	synonymous_variant	6/9	1	NM_001369369.1	P1
FOXN1	ENST00000226247.2 linkuse as main transcript	c.852T>C	p.Leu284=	synonymous_variant	5/8	1		P1
RSKR	ENST00000481916.6 linkuse as main transcript	c.*1195+73281A>G		intron_variant, NMD_transcript_variant		1			Q96LW2-2
FOXN1	ENST00000577936.2 linkuse as main transcript	c.852T>C	p.Leu284=	synonymous_variant	6/9	4		P1

Frequencies

GnomAD3 genomes

AF:

0.0912

AC:

13864

AN:

151968

Hom.:

861

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0527

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.0608

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.0747

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0824

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.114

AC:

28548

AN:

251460

Hom.:

2339

AF XY:

0.107

AC XY:

14502

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0509

Gnomad AMR exome

AF:

0.255

Gnomad ASJ exome

AF:

0.0568

Gnomad EAS exome

AF:

0.226

Gnomad SAS exome

AF:

0.0732

Gnomad FIN exome

AF:

0.0966

Gnomad NFE exome

AF:

0.0810

Gnomad OTH exome

AF:

0.0989

GnomAD4 exome

AF:

0.0905

AC:

131357

AN:

1451360

Hom.:

7544

Cov.:

AF XY:

0.0889

AC XY:

64242

AN XY:

722770

show subpopulations

Gnomad4 AFR exome

AF:

0.0498

Gnomad4 AMR exome

AF:

0.250

Gnomad4 ASJ exome

AF:

0.0551

Gnomad4 EAS exome

AF:

0.248

Gnomad4 SAS exome

AF:

0.0728

Gnomad4 FIN exome

AF:

0.0930

Gnomad4 NFE exome

AF:

0.0817

Gnomad4 OTH exome

AF:

0.0924

GnomAD4 genome

AF:

0.0913

AC:

13880

AN:

152086

Hom.:

865

Cov.:

AF XY:

0.0954

AC XY:

7094

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0528

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.0608

Gnomad4 EAS

AF:

0.226

Gnomad4 SAS

AF:

0.0735

Gnomad4 FIN

AF:

0.102

Gnomad4 NFE

AF:

0.0824

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.0869

Hom.:

1596

Bravo

AF:

0.0971

Asia WGS

AF:

0.115

AC:

399

AN:

3478

EpiCase

AF:

0.0817

EpiControl

AF:

0.0795

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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	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: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

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.2

DANN

Benign

0.71

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