chr17-28530770-T-C

Variant names:

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

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 (★★). The gene FOXN1 is included in the ClinGen Criteria Specification Registry.

• 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:7 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

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

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 VariationId 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.

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.852T>C	p.Leu284Leu	synonymous	Exon 6 of 9	NP_001356298.1	O15353
	FOXN1	NM_003593.3		c.852T>C	p.Leu284Leu	synonymous	Exon 5 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.852T>C	p.Leu284Leu	synonymous	Exon 6 of 9	ENSP00000464645.1	O15353
	FOXN1	ENST00000226247.2	TSL:1	c.852T>C	p.Leu284Leu	synonymous	Exon 5 of 8	ENSP00000226247.2	O15353
	RSKR	ENST00000481916.6	TSL:1	n.*1195+73281A>G		intron	N/A	ENSP00000436369.2	Q96LW2-2

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	T-cell immunodeficiency, congenital alopecia, and nail dystrophy (2)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;