rs143844274

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP7BS1

This summary comes from the ClinGen Evidence Repository: NM_001369369.1(FOXN1):c.930A>G (p.Thr310=) is a synonymous variant. SpliceAI predicts no impact to the splice consensus sequence (delta score 0.00) nor the creation of a new splice site (delta score<=0.01) and the nucleotide is not highly conserved (phyloP score -1.54) (BP4, BP7). The gnomADv2.1.1 PopMax filtering AF is 0.002017 based on 66/24964alleles in the African/African American population, which is above the >0.00141 threshold for BS1. In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BS1, BP4, and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459411/MONDO:0011132/113

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

FOXN1
NM_001369369.1 splice_region, synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: -1.47

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 -6 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1 link	c.930A>G	p.Thr310Thr	splice_region_variant, synonymous_variant	Exon 7 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXN1	ENST00000579795.6 link	c.930A>G	p.Thr310Thr	splice_region_variant, synonymous_variant	Exon 7 of 9	1	NM_001369369.1	ENSP00000464645.1	O15353
FOXN1	ENST00000226247.2 link	c.930A>G	p.Thr310Thr	splice_region_variant, synonymous_variant	Exon 6 of 8	1		ENSP00000226247.2	O15353
RSKR	ENST00000481916.6 link	n.*1195+69718T>C		intron_variant	Intron 7 of 7	1		ENSP00000436369.2	Q96LW2-2
FOXN1	ENST00000577936.2 link	c.930A>G	p.Thr310Thr	splice_region_variant, synonymous_variant	Exon 7 of 9	4		ENSP00000462159.2	O15353J3KRT9

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251482

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152280

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000379

Hom.:

Bravo

AF:

0.000763

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

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:2

Jul 29, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001369369.1(FOXN1):c.930A>G (p.Thr310=) is a synonymous variant. SpliceAI predicts no impact to the splice consensus sequence (delta score 0.00) nor the creation of a new splice site (delta score<=0.01) and the nucleotide is not highly conserved (phyloP score -1.54) (BP4, BP7). The gnomADv2.1.1 PopMax filtering AF is 0.002017 based on 66/24964 alleles in the African/African American population, which is above the >0.00141 threshold for BS1. In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BS1, BP4, and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FOXN1-related disorder

Benign:1

Jun 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.037

DANN

Benign

0.43

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