rs61749867

Variant names:

• chr17-28534859-C-T
• rs61749867
• NM_001369369.1:c.1288C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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

Specifications for FOXN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369369.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN1	NM_001369369.1	MANE Select	c.1288C>T	p.Pro430Ser	missense	Exon 8 of 9	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.1288C>T	p.Pro430Ser	missense	Exon 7 of 8	NP_003584.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXN1	ENST00000579795.6	TSL:1 MANE Select	c.1288C>T	p.Pro430Ser	missense	Exon 8 of 9	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.1288C>T	p.Pro430Ser	missense	Exon 7 of 8	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1195+69192G>A		intron	N/A	ENSP00000436369.2	Q96LW2-2

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

GnomAD2 exomes AF: 0.0308 AC: 7734 AN: 250710 AF XY: 0.0309

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 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

African (AFR) AF: 0.00565 AC: 189 AN: 33478

American (AMR) AF: 0.00941 AC: 421 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00800 AC: 209 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.00504 AC: 435 AN: 86254

European-Finnish (FIN) AF: 0.0713 AC: 3809 AN: 53400

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.0509 AC: 56551 AN: 1111908

Other (OTH) AF: 0.0321 AC: 1940 AN: 60386

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

African (AFR) AF: 0.00898 AC: 373 AN: 41552

American (AMR) AF: 0.0137 AC: 210 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.0724 AC: 769 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3077 AN: 68012

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0370 Hom.: 276

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.52	N
PhyloP100		-0.20
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.056
MPC		0.014
ClinPred		0.0052	T
GERP RS		2.3
Varity_R		0.030
gMVP		0.29
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61749867; hg19: chr17-26861877;