dbSNP rs532648: FOXN1:p.Ala599Thr (chr17-28537284-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001369369.1(FOXN1):c.1795G>A(p.Ala599Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXN1
NM_001369369.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0710

Variant links:

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]

FOXN1 links:

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]

RSKR links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05055937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1 link	c.1795G>A	p.Ala599Thr	missense_variant	Exon 9 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXN1	ENST00000579795.6 link	c.1795G>A	p.Ala599Thr	missense_variant	Exon 9 of 9	1	NM_001369369.1	ENSP00000464645.1	O15353
FOXN1	ENST00000226247.2 link	c.1795G>A	p.Ala599Thr	missense_variant	Exon 8 of 8	1		ENSP00000226247.2	O15353
RSKR	ENST00000481916.6 link	n.*1195+66767C>T		intron_variant	Intron 7 of 7	1		ENSP00000436369.2	Q96LW2-2
FOXN1	ENST00000577936.2 link	c.1795G>A	p.Ala599Thr	missense_variant	Exon 9 of 9	4		ENSP00000462159.2	O15353J3KRT9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Benign

4.3

DANN

Benign

0.91

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

.;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.39

.;N

REVEL

Benign

0.18

Sift

Benign

0.35

.;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;B

Vest4

0.098

MutPred

0.27

Gain of glycosylation at A599 (P = 0.0035);Gain of glycosylation at A599 (P = 0.0035);

MVP

0.20

MPC

0.014

ClinPred

0.16

GERP RS

2.2

Varity_R

0.031

gMVP

0.13

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over