Genetic Variant NM_001369369.1:c.35C>G (chr17-28524004-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001369369.1(FOXN1):c.35C>G(p.Thr12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. T12T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

FOXN1
NM_001369369.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19770718).

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.35C>G	p.Thr12Arg	missense	Exon 2 of 9	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.35C>G	p.Thr12Arg	missense	Exon 1 of 8	NP_003584.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXN1	ENST00000579795.6	TSL:1 MANE Select	c.35C>G	p.Thr12Arg	missense	Exon 2 of 9	ENSP00000464645.1	O15353
FOXN1	ENST00000226247.2	TSL:1	c.35C>G	p.Thr12Arg	missense	Exon 1 of 8	ENSP00000226247.2	O15353
RSKR	ENST00000481916.6	TSL:1	n.*1196-67895G>C		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

T-cell immunodeficiency, congenital alopecia, and nail dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.013

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.71

M_CAP

Benign

0.045

MetaRNN

Benign

0.20

MetaSVM

Uncertain

-0.049

MutationAssessor

Benign

0.55

PhyloP100

3.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.49

REVEL

Benign

0.26

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

0.047

Vest4

0.49

MutPred

0.11

Loss of phosphorylation at T12 (P = 0.038)

MVP

0.57

MPC

0.21

ClinPred

0.82

GERP RS

5.0

PromoterAI

-0.078

Neutral

(source)

Varity_R

0.25

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over