rs181483148

chr17-28535189-G-Achr17-28535189-G-Cchr17-28535189-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_001369369.1(FOXN1):c.1618G>A(p.Asp540Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,613,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.49

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3656662).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000171 (26/152330) while in subpopulation NFE AF= 0.000382 (26/68038). AF 95% confidence interval is 0.000267. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN1	NM_001369369.1	c.1618G>A	p.Asp540Asn	missense_variant	8/9	ENST00000579795.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN1	ENST00000579795.6	c.1618G>A	p.Asp540Asn	missense_variant	8/9	1	NM_001369369.1	P1
FOXN1	ENST00000226247.2	c.1618G>A	p.Asp540Asn	missense_variant	7/8	1		P1
RSKR	ENST00000481916.6	c.*1195+68862C>T		intron_variant, NMD_transcript_variant		1
FOXN1	ENST00000577936.2	c.1618G>A	p.Asp540Asn	missense_variant	8/9	4		P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000157 AC: 39 AN: 249174 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 134874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.000320

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000268 AC: 392 AN: 1460844 Hom.: 0 Cov.: 35 AF XY: 0.000256 AC XY: 186 AN XY: 726696

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000339

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000243 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 540 of the FOXN1 protein (p.Asp540Asn). This variant is present in population databases (rs181483148, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FOXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 536428). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FOXN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	FOXN1: BP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.079	T;T
Polyphen		1.0	D;D
Vest4		0.54
MVP		0.84
MPC		0.11
ClinPred		0.15	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.26

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: rs181483148; hg19: chr17-26862207;