chr17-28534786-C-T

Variant names:

• chr17-28534786-C-T
• rs116778145
• NM_001369369.1:c.1215C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003593.3(FOXN1):​c.1215C>T​(p.Ser405Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,613,632 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: FOXN1 NM_003593.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.375
• 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-28534786-C-T is Benign according to our data. Variant chr17-28534786-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.375 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00529 (806/152274) while in subpopulation AFR AF = 0.018 (749/41562). AF 95% confidence interval is 0.017. There are 12 homozygotes in GnomAd4. There are 387 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003593.3. 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.1215C>T	p.Ser405Ser	synonymous	Exon 8 of 9	NP_001356298.1
	FOXN1	NM_003593.3		c.1215C>T	p.Ser405Ser	synonymous	Exon 7 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.1215C>T	p.Ser405Ser	synonymous	Exon 8 of 9	ENSP00000464645.1
	FOXN1	ENST00000226247.2	TSL:1	c.1215C>T	p.Ser405Ser	synonymous	Exon 7 of 8	ENSP00000226247.2
	RSKR	ENST00000481916.6	TSL:1	n.*1195+69265G>A		intron	N/A	ENSP00000436369.2

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152156 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00133 AC: 329 AN: 247152 AF XY: 0.000984

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.00130

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: 0.000497

GnomAD4 exome AF: 0.000497 AC: 727 AN: 1461358 Hom.: 7 Cov.: 35 AF XY: 0.000422 AC XY: 307 AN XY: 726958

African (AFR) AF: 0.0176 AC: 590 AN: 33474

American (AMR) AF: 0.00139 AC: 62 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111730

Other (OTH) AF: 0.00111 AC: 67 AN: 60370

GnomAD4 genome AF: 0.00529 AC: 806 AN: 152274 Hom.: 12 Cov.: 33 AF XY: 0.00520 AC XY: 387 AN XY: 74440

African (AFR) AF: 0.0180 AC: 749 AN: 41562

American (AMR) AF: 0.00307 AC: 47 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00599

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116778145; hg19: chr17-26861804;