chr17-28537186-C-A

Variant names:

• chr17-28537186-C-A
• rs12603884
• NM_001369369.1:c.1697C>A

Variant summary

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

The NM_001369369.1(FOXN1):​c.1697C>A​(p.Pro566Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.30

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.1697C>A	p.Pro566Gln	missense_variant	Exon 9 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.1697C>A	p.Pro566Gln	missense_variant	Exon 9 of 9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.1697C>A	p.Pro566Gln	missense_variant	Exon 8 of 8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+66865G>T		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.1697C>A	p.Pro566Gln	missense_variant	Exon 9 of 9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;D
Eigen	Benign	0.043
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.73	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.5	.;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.95	P;P
Vest4		0.53
MutPred		0.30		Loss of glycosylation at P566 (P = 0.0046);Loss of glycosylation at P566 (P = 0.0046);
MVP		0.69
MPC		0.096
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.63
gMVP		0.51

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: rs12603884; hg19: chr17-26864204;