Genetic Variant FOXN1:c.-14-137_-14-124dupTCTCTCTCTCTCTC (chr17-28523792-T-TTCTCTCTCTCTCTC) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001369369.1(FOXN1):c.-14-137_-14-124dupTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 650,380 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene FOXN1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

FOXN1
NM_001369369.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0970

Publications

1 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:

Genome browser will be placed here

ACMG classification

Specifications for FOXN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000873 (126/144328) while in subpopulation AFR AF = 0.00225 (85/37732). AF 95% confidence interval is 0.00187. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.-14-137_-14-124dupTCTCTCTCTCTCTC		intron	N/A	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.-178_-177insTCTCTCTCTCTCTC		upstream_gene	N/A	NP_003584.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FOXN1	ENST00000579795.6	TSL:1 MANE Select	c.-14-164_-14-163insTCTCTCTCTCTCTC	intron	N/A	ENSP00000464645.1	O15353
RSKR	ENST00000481916.6	TSL:1	n.1196-67684_1196-67683insGAGAGAGAGAGAGA	intron	N/A	ENSP00000436369.2	Q96LW2-2
FOXN1	ENST00000577936.2	TSL:4	c.-9-169_-9-168insTCTCTCTCTCTCTC	intron	N/A	ENSP00000462159.2	O15353

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

127

AN:

144228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000978

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000838

Gnomad SAS

AF:

0.000675

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0129

Gnomad NFE

AF:

0.000254

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000217

AC:

110

AN:

506052

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

272078

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00171

AC:

AN:

14044

American (AMR)

AF:

0.000214

AC:

AN:

28072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17594

East Asian (EAS)

AF:

0.000195

AC:

AN:

30846

South Asian (SAS)

AF:

0.000508

AC:

AN:

57038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2400

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

292576

Other (OTH)

AF:

0.000214

AC:

AN:

27978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.361

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000873

AC:

126

AN:

144328

Hom.:

Cov.:

AF XY:

0.000858

AC XY:

AN XY:

69934

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

37732

American (AMR)

AF:

0.000977

AC:

AN:

14330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.000840

AC:

AN:

4764

South Asian (SAS)

AF:

0.000676

AC:

AN:

4438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9668

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000255

AC:

AN:

66794

Other (OTH)

AF:

0.00

AC:

AN:

1994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.097

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

17-28523792-TTCTCTCTCTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over