rs12449554

Variant names:

• chr17-28530770-T-C
• rs12449554
• NM_001369369.1:c.852T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-28530770-T-C
• chr17-28530770-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369369.1(FOXN1):​c.852T>C​(p.Leu284Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,603,446 control chromosomes in the GnomAD database, including 8,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (865 hom., cov: 32)
  • Exomes 𝑓: 0.091 (7544 hom.)
• Consequence: FOXN1 NM_001369369.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.167
• Publications: 14 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=-0.51).
• BP6: Variant 17-28530770-T-C is Benign according to our data. Variant chr17-28530770-T-C is described in ClinVar as [Benign]. Clinvar id is 322425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.167 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXN1	NM_001369369.1	c.852T>C	p.Leu284Leu	synonymous_variant	Exon 6 of 9	ENST00000579795.6	NP_001356298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXN1	ENST00000579795.6	c.852T>C	p.Leu284Leu	synonymous_variant	Exon 6 of 9	1	NM_001369369.1	ENSP00000464645.1
FOXN1	ENST00000226247.2	c.852T>C	p.Leu284Leu	synonymous_variant	Exon 5 of 8	1		ENSP00000226247.2
RSKR	ENST00000481916.6	n.*1195+73281A>G		intron_variant	Intron 7 of 7	1		ENSP00000436369.2
FOXN1	ENST00000577936.2	c.852T>C	p.Leu284Leu	synonymous_variant	Exon 6 of 9	4		ENSP00000462159.2

Frequencies

GnomAD3 genomes AF: 0.0912 AC: 13864 AN: 151968 Hom.: 861 Cov.: 32

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0824

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.114 AC: 28548 AN: 251460 AF XY: 0.107

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.0568

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.0966

Gnomad NFE exome AF: 0.0810

Gnomad OTH exome AF: 0.0989

GnomAD4 exome AF: 0.0905 AC: 131357 AN: 1451360 Hom.: 7544 Cov.: 28 AF XY: 0.0889 AC XY: 64242 AN XY: 722770

African (AFR) AF: 0.0498 AC: 1659 AN: 33304

American (AMR) AF: 0.250 AC: 11176 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 1438 AN: 26076

East Asian (EAS) AF: 0.248 AC: 9830 AN: 39638

South Asian (SAS) AF: 0.0728 AC: 6267 AN: 86046

European-Finnish (FIN) AF: 0.0930 AC: 4968 AN: 53392

Middle Eastern (MID) AF: 0.0662 AC: 381 AN: 5758

European-Non Finnish (NFE) AF: 0.0817 AC: 90092 AN: 1102408

Other (OTH) AF: 0.0924 AC: 5546 AN: 60044

GnomAD4 genome AF: 0.0913 AC: 13880 AN: 152086 Hom.: 865 Cov.: 32 AF XY: 0.0954 AC XY: 7094 AN XY: 74348

African (AFR) AF: 0.0528 AC: 2192 AN: 41480

American (AMR) AF: 0.194 AC: 2962 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1164 AN: 5158

South Asian (SAS) AF: 0.0735 AC: 354 AN: 4814

European-Finnish (FIN) AF: 0.102 AC: 1084 AN: 10586

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0824 AC: 5602 AN: 67992

Other (OTH) AF: 0.104 AC: 220 AN: 2112

Alfa AF: 0.0873 Hom.: 3227

Bravo AF: 0.0971

Asia WGS AF: 0.115 AC: 399 AN: 3478

EpiCase AF: 0.0817

EpiControl AF: 0.0795

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 25, 2015

GeneDx

Significance: 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. -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.2
DANN	Benign	0.71
PhyloP100		0.17
Mutation Taster		=93/7	polymorphism (auto)

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: rs12449554; hg19: chr17-26857788; COSMIC: COSV56880976;