rs115771646

Variant names:

• chr17-28534996-G-A
• rs115771646
• NM_001369369.1:c.1425G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-28534996-G-A
• chr17-28534996-G-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_001369369.1(FOXN1):​c.1425G>A​(p.Pro475Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,958 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P475P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (7 hom.)
• Consequence: FOXN1 NM_001369369.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0370
• Publications: 1 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=-0.58).
• BP6: Variant 17-28534996-G-A is Benign according to our data. Variant chr17-28534996-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00546 (831/152296) while in subpopulation AFR AF = 0.0185 (770/41556). AF 95% confidence interval is 0.0174. There are 12 homozygotes in GnomAd4. There are 402 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.1425G>A	p.Pro475Pro	synonymous_variant	Exon 8 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.1425G>A	p.Pro475Pro	synonymous_variant	Exon 8 of 9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.1425G>A	p.Pro475Pro	synonymous_variant	Exon 7 of 8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+69055C>T		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.1425G>A	p.Pro475Pro	synonymous_variant	Exon 8 of 9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 824 AN: 152178 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00140 AC: 351 AN: 249902 AF XY: 0.00105

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000569 AC: 832 AN: 1461662 Hom.: 7 Cov.: 35 AF XY: 0.000485 AC XY: 353 AN XY: 727146

African (AFR) AF: 0.0182 AC: 610 AN: 33478

American (AMR) AF: 0.00139 AC: 62 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1111938

Other (OTH) AF: 0.00126 AC: 76 AN: 60384

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152296 Hom.: 12 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74460

African (AFR) AF: 0.0185 AC: 770 AN: 41556

American (AMR) AF: 0.00327 AC: 50 AN: 15300

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00622

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

T-cell immunodeficiency, congenital alopecia, and nail dystrophy Benign:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Sep 01, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.3
DANN	Benign	0.81
PhyloP100		0.037
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs115771646; hg19: chr17-26862014;