rs61749867

Positions:

• chr17-28534859-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 NM_001369369.1(FOXN1):c.1288C>T (p.Pro430Ser) missense variant has a gnomAD popmax filtering allele frequency of 0.04634 based on 6036/128650 alleles in the European (non-Finnish) population, which is greater than >0.00447 and thus meets BA1. The variant has a REVEL score of 0.168, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. Of note, this variant has been reported (PMID:31566583) in the context of T cell immunodeficiency, however it was in trans with c.1465del which is considered to be the causal variant. Pro430Ser is not considered to contribute to the phenotype, which is consistent with functional studies of the variant which found the variant had no significant effect on expression or Luciferase activity compared to WT (PMID:31566583) and a heterozygous mouse model was unaffected (PMID:37419334). 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, as specified by the ClinGen SCID VCEP: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8459494/MONDO:0011132/113

• Frequency:
  • Genomes: 𝑓 0.030 (111 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1782 hom.)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -0.200

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.1288C>T	p.Pro430Ser	missense_variant	8/9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.1288C>T	p.Pro430Ser	missense_variant	8/9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.1288C>T	p.Pro430Ser	missense_variant	7/8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+69192G>A		intron_variant		1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.1288C>T	p.Pro430Ser	missense_variant	8/9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4515 AN: 152156 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.00900

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0308 AC: 7734 AN: 250710 Hom.: 207 AF XY: 0.0309 AC XY: 4193 AN XY: 135556

Gnomad AFR exome AF: 0.00685

Gnomad AMR exome AF: 0.00926

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00497

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0474

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0435 AC: 63586 AN: 1461742 Hom.: 1782 Cov.: 35 AF XY: 0.0421 AC XY: 30581 AN XY: 727172

Gnomad4 AFR exome AF: 0.00565

Gnomad4 AMR exome AF: 0.00941

Gnomad4 ASJ exome AF: 0.00800

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00504

Gnomad4 FIN exome AF: 0.0713

Gnomad4 NFE exome AF: 0.0509

Gnomad4 OTH exome AF: 0.0321

GnomAD4 genome AF: 0.0297 AC: 4515 AN: 152274 Hom.: 111 Cov.: 33 AF XY: 0.0308 AC XY: 2290 AN XY: 74456

Gnomad4 AFR AF: 0.00898

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0724

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0399 Hom.: 205

Bravo AF: 0.0239

TwinsUK AF: 0.0512 AC: 190

ALSPAC AF: 0.0511 AC: 197

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0402 AC: 346

ExAC AF: 0.0316 AC: 3836

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0379

EpiControl AF: 0.0384

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2016	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 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jul 29, 2024	The NM_001369369.1(FOXN1):c.1288C>T (p.Pro430Ser) missense variant has a gnomAD popmax filtering allele frequency of 0.04634 based on 6036/128650 alleles in the European (non-Finnish) population, which is greater than >0.00447 and thus meets BA1. The variant has a REVEL score of 0.168, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. Of note, this variant has been reported (PMID: 31566583) in the context of T cell immunodeficiency, however it was in trans with c.1465del which is considered to be the causal variant. Pro430Ser is not considered to contribute to the phenotype, which is consistent with functional studies of the variant which found the variant had no significant effect on expression or Luciferase activity compared to WT (PMID: 31566583) and a heterozygous mouse model was unaffected (PMID: 37419334). 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, as specified by the ClinGen SCID VCEP: BA1, BP4. -
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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.64	.;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.52	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.060	.;N
REVEL	Benign	0.17
Sift	Benign	0.19	.;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;B
Vest4		0.056
MPC		0.014
ClinPred		0.0052	T
GERP RS		2.3
Varity_R		0.030
gMVP		0.29

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: rs61749867; hg19: chr17-26861877;