chr17-28524925-C-G

Variant names:

• chr17-28524925-C-G
• rs62640040
• NM_001369369.1:c.546C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001369369.1(FOXN1):​c.546C>G​(p.Asn182Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,320 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N182N) has been classified as Likely benign. The gene FOXN1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.546C>G	p.Asn182Lys	missense	Exon 3 of 9	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.546C>G	p.Asn182Lys	missense	Exon 2 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.546C>G	p.Asn182Lys	missense	Exon 3 of 9	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.546C>G	p.Asn182Lys	missense	Exon 2 of 8	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1196-68816G>C		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248818 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460320 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	1.5
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.24
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.23	T
Polyphen		0.83	P
Vest4		0.49
MutPred		0.60		Gain of methylation at N182 (P = 4e-04)
MVP		0.71
MPC		0.21
ClinPred		0.80	D
GERP RS		2.0
Varity_R		0.22
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62640040; hg19: chr17-26851943;