17-28524007-T-C

Position:

• chr17-28524007-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001369369.1(FOXN1):​c.38T>C​(p.Leu13Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L13L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXN1 NM_001369369.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4141441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN1	NM_001369369.1	c.38T>C	p.Leu13Pro	missense_variant	2/9	ENST00000579795.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN1	ENST00000579795.6	c.38T>C	p.Leu13Pro	missense_variant	2/9	1	NM_001369369.1	P1
FOXN1	ENST00000226247.2	c.38T>C	p.Leu13Pro	missense_variant	1/8	1		P1
RSKR	ENST00000481916.6	c.*1196-67898A>G		intron_variant, NMD_transcript_variant		1
FOXN1	ENST00000577936.2	c.38T>C	p.Leu13Pro	missense_variant	2/9	4		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

The c.38T>C (p.L13P) alteration is located in exon 1 (coding exon 1) of the FOXN1 gene. This alteration results from a T to C substitution at nucleotide position 38, causing the leucine (L) at amino acid position 13 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.67	T;.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	0.81	.;L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	.;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	.;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.79, 0.77
MutPred		0.11		Loss of stability (P = 0.061);Loss of stability (P = 0.061);Loss of stability (P = 0.061);
MVP		0.73
MPC		0.80
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.37
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-26851025;